Professor of Pathology at the Stanford University Medical Center

Publications

  • MYB-activated models for testing therapeutic agents in adenoid cystic carcinoma. Oral oncology Jiang, Y., Gao, R., Cao, C., Forbes, L., Li, J., Freeberg, S., Fredenburg, K. M., Justice, J. M., Silver, N. L., Wu, L., Varma, S., West, R., Licht, J. D., Zajac-Kaye, M., Kentsis, A., Kaye, F. J. 2019; 98: 147–55

    Abstract

    OBJECTIVE: There are no effective systemic therapies for adenoid cystic cancer (ACC) and lack of tumor lines and mouse models have hindered drug development.We aim to develop MYB-activated models for testing new therapeutic agents.MATERIALS AND METHODS: We studied new ACC patient-derived xenograft (PDX) models and generated a matched cell line from one patient. In addition, we generated a genetically-engineered MYB-NFIB mouse model (GEMM) that was crossed with Ink4a+/-/Arf+/- mice to study tumor spectrum and obtain tumor lines. Using human and murine ACC-like tumor lines, we analyzed MYB expression by RNA-Seq and immunoblot and tested efficacy of new MYB inhibitors.RESULTS: We detected MYB-NFIB transcripts in both UFH1 and UFH2 PDX and observed tumor inhibition by MYB depletion using shRNA in vivo. We observed rapid loss of MYB expression when we cultured UFH1 in vitro, but were able to generate a UFH2 tumor cell line that retained MYB expression for 6 months. RNA-Seq expression detected an ACC-like mRNA signature in PDX samples and we confirmed an identical KMT2A/MLL variant in UFH2 PDX, matched cell line, and primary biopsy. Although the predominant phenotype of the MYB-NFIB GEMM was B-cell leukemia, we also generated a MYB-activated ACC-like mammary tumor cell line. We observed tumor inhibition using a novel MYB peptidomimetic in both human and murine tumor models.CONCLUSIONS: We generated and studied new murine and human MYB-activated tumor samples and detected growth inhibition with MYB peptidomimetics. These data provide tools to define treatment strategies for patients with advanced MYB-activated ACC.

    View details for DOI 10.1016/j.oraloncology.2019.09.005

    View details for PubMedID 31606723

  • MIBI-TOF: A multiplexed imaging platform relates cellular phenotypes and tissue structure. Science advances Keren, L., Bosse, M., Thompson, S., Risom, T., Vijayaragavan, K., McCaffrey, E., Marquez, D., Angoshtari, R., Greenwald, N. F., Fienberg, H., Wang, J., Kambham, N., Kirkwood, D., Nolan, G., Montine, T. J., Galli, S. J., West, R., Bendall, S. C., Angelo, M. 2019; 5 (10): eaax5851

    Abstract

    Understanding tissue structure and function requires tools that quantify the expression of multiple proteins while preserving spatial information. Here, we describe MIBI-TOF (multiplexed ion beam imaging by time of flight), an instrument that uses bright ion sources and orthogonal time-of-flight mass spectrometry to image metal-tagged antibodies at subcellular resolution in clinical tissue sections. We demonstrate quantitative, full periodic table coverage across a five-log dynamic range, imaging 36 labeled antibodies simultaneously with histochemical stains and endogenous elements. We image fields of view up to 800 mum * 800 mum at resolutions down to 260 nm with sensitivities approaching single-molecule detection. We leverage these properties to interrogate intrapatient heterogeneity in tumor organization in triple-negative breast cancer, revealing regional variability in tumor cell phenotypes in contrast to a structured immune response. Given its versatility and sample back-compatibility, MIBI-TOF is positioned to leverage existing annotated, archival tissue cohorts to explore emerging questions in cancer, immunology, and neurobiology.

    View details for DOI 10.1126/sciadv.aax5851

    View details for PubMedID 31633026

  • Gene-expression profiling of single cells from archival tissue with laser-capture microdissection and Smart-3SEQ. Genome research Foley, J. W., Zhu, C., Jolivet, P., Zhu, S. X., Lu, P., Meaney, M. J., West, R. B. 2019

    Abstract

    RNA sequencing (RNA-seq) is a sensitive and accurate method for quantifying gene expression. Small samples or those whose RNA is degraded, such as formalin-fixed, paraffin-embedded (FFPE) tissue, remain challenging to study with nonspecialized RNA-seq protocols. Here we present a new method, Smart-3SEQ, that accurately quantifies transcript abundance even with small amounts of total RNA and effectively characterizes small samples extracted by laser-capture microdissection (LCM) from FFPE tissue. We also obtain distinct biological profiles from FFPE single cells, which have been impossible to study with previous RNA-seq protocols, and we use these data to identify possible new macrophage phenotypes associated with the tumor microenvironment. We propose Smart-3SEQ as a highly cost-effective method to enable large gene-expression profiling experiments unconstrained by sample size and tissue availability. In particular, Smart-3SEQ's compatibility with FFPE tissue unlocks an enormous number of archived clinical samples, and combined with LCM it allows unprecedented studies of small cell populations and single cells isolated by their in situ context.

    View details for DOI 10.1101/gr.234807.118

    View details for PubMedID 31519740

  • Race and risk of subsequent aggressive breast cancer following ductal carcinoma in situ. Cancer Liu, Y., West, R., Weber, J. D., Colditz, G. A. 2019

    Abstract

    BACKGROUND: General populations of black women have a higher risk of developing breast cancer negative for both estrogen receptor (ER) and progesterone receptor (PR) in comparison with white counterparts. Racial differences remain unknown in the risk of developing aggressive invasive breast cancer (IBC) that is characterized by negativity for both ER and PR (ER-PR-) or higher 21-gene recurrence scores after ductal carcinoma in situ (DCIS).METHODS: This study identified 163,892 women (10.5% black, 9.8% Asian, and 8.6% Hispanic) with incident DCIS between 1990 and 2015 from the Surveillance, Epidemiology, and End Results data sets. Cox proportional hazards regression was used to estimate hazards ratios (HRs) of subsequent IBC classified by the hormone receptor status and 21-gene recurrence scores.RESULTS: During a median follow-up of 90months, 8333 women developed IBC. In comparison with white women, the adjusted HR of subsequent ER-PR- breast cancer was 1.86 (95% confidence interval [CI], 1.57-2.20) for black women (absolute 10-year difference, 2.2%) and 1.40 (95% CI, 1.14-1.71) for Asian women (absolute 10-year difference, 0.4%); this was stronger than the associations for ER+ and/or PR+ subtypes (Pheterogeneity =.0004). The 21-gene recurrence scores of subsequent early-stage, ER+ IBCs varied by race/ethnicity (Pheterogeneity =.057); black women were more likely than white women to have a recurrence score of 26 or higher (HR, 1.38; 95% CI, 1.00-1.92). No significant difference was observed in the risks of subsequent IBC subtypes for Hispanic women.CONCLUSIONS: Black and Asian women with DCIS had higher risks of developing biologically aggressive IBC than white counterparts. This should be considered in treatment decisions for black and Asian patients with DCIS.

    View details for DOI 10.1002/cncr.32200

    View details for PubMedID 31120565

  • Increased Galectin-1 Expression in Thymic Epithelial Tumors CLINICAL LUNG CANCER Riess, J. W., Kong, C. S., West, R. B., Padda, S. K., Neal, J. W., Wakelee, H. A., Le, Q. 2019; 20 (3): E356–E361
  • YAP-independent mechanotransduction drives breast cancer progression NATURE COMMUNICATIONS Lee, J. Y., Chang, J. K., Dominguez, A. A., Lee, H., Nam, S., Chang, J., Varma, S., Qi, L. S., West, R. B., Chaudhuri, O. 2019; 10
  • The HTN3-MSANTD3 Fusion Gene Defines a Subset of Acinic Cell Carcinoma of the Salivary Gland AMERICAN JOURNAL OF SURGICAL PATHOLOGY Andreasen, S., Varma, S., Barasch, N., Thompson, L. R., Miettinen, M., Rooper, L., Stelow, E. B., Agander, T. K., Seethala, R. R., Chiosea, S. I., Homoe, P., Wessel, I., Larsen, S. R., Erentaite, D., Bishop, J. A., Ulhoi, B. P., Kiss, K., Melchior, L. C., Pollack, J. R., West, R. B. 2019; 43 (4): 489–96
  • Systematic Analysis of GATA3 Expression in 530 Primary Mesenchymal Neoplasms Wei, C., Charville, G., Bean, G., Troxell, M., Allison, K., Van de Rijn, M., West, R. NATURE PUBLISHING GROUP. 2019
  • Systematic Analysis of GATA3 Expression in 530 Primary Mesenchymal Neoplasms Wei, C., Charville, G., Bean, G., Troxell, M., Allison, K., Van de Rijn, M., West, R. NATURE PUBLISHING GROUP. 2019
  • Most canine ameloblastomas harbor HRAS mutations, providing a novel large-animal model of RAS-driven cancer. Oncogenesis Saffari, P. S., Vapniarsky, N., Pollack, A. S., Gong, X., Vennam, S., Pollack, A. J., Verstraete, F. J., West, R. B., Arzi, B., Pollack, J. R. 2019; 8 (2): 11

    Abstract

    Canine acanthomatous ameloblastomas (CAA), analogs of human ameloblastoma, are oral tumors of odontogenic origin for which the genetic drivers have remained undefined. By whole-exome sequencing, we have now discovered recurrent HRAS and BRAF activating mutations, respectively, in 63% and 8% of CAA. Notably, cell lines derived from CAA with HRAS mutation exhibit marked sensitivity to MAP kinase (MAPK) pathway inhibitors, which constrain cell proliferation and drive ameloblast differentiation. Our findings newly identify a large-animal spontaneous cancer model to study the progression and treatment of RAS-driven cancer. More broadly, our study highlights the translational potential of canine cancer genome sequencing to benefit both humans and their companion animals.

    View details for PubMedID 30741938

  • ERBB2 copy number analysis of invasive breast carcinoma using digital droplet PCR and targeted next-generation sequencing: A focus on 'non-classical' HER2 FISH groups using the 2018 ASCO/CAP HER2 testing guideline Yang, S., Bouhlal, Y., De La Vega, F. M., Ballard, M., West, R. B., Sibley, R. K., Kuo, C. J., Vilborg, A., Allison, K. H. AMER ASSOC CANCER RESEARCH. 2019
  • Development of a machine learning-based classifier for Oncotype DX (R) category prediction in a population of lymph node positive breast carcinoma patients Beca, F., Yang, S., Gruber, J. G., Barry-Holson, K., West, R., Wen, H. Y., Allison, K. H. AMER ASSOC CANCER RESEARCH. 2019
  • Blood transcriptome and clonal T cell correlates of response and nonresponse to eltrombopag therapy in a cohort of patients with chronic immune thrombocytopenia. Haematologica Zhang, H., Zhang, B. M., Guo, X., Xu, L., You, X., West, R. B., Bussel, J. B., Zehnder, J. L. 2019

    View details for DOI 10.3324/haematol.2019.226688

    View details for PubMedID 31296576

  • YAP-independent mechanotransduction drives breast cancer progression. Nature communications Lee, J. Y., Chang, J. K., Dominguez, A. A., Lee, H. P., Nam, S., Chang, J., Varma, S., Qi, L. S., West, R. B., Chaudhuri, O. 2019; 10 (1): 1848

    Abstract

    Increased tissue stiffness is a driver of breast cancer progression. The transcriptional regulator YAP is considered a universal mechanotransducer, based largely on 2D culture studies. However, the role of YAP during in vivo breast cancer remains unclear. Here, we find that mechanotransduction occurs independently of YAP in breast cancer patient samples and mechanically tunable 3D cultures. Mechanistically, the lack of YAP activity in 3D culture and in vivo is associated with the absence of stress fibers and an order of magnitude decrease in nuclear cross-sectional area relative to 2D culture. This work highlights the context-dependent role of YAP in mechanotransduction, and establishes that YAP does not mediate mechanotransduction in breast cancer.

    View details for PubMedID 31015465

  • Publisher Correction: Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy. Nature communications Caswell-Jin, J. L., McNamara, K., Reiter, J. G., Sun, R., Hu, Z., Ma, Z., Ding, J., Suarez, C. J., Tilk, S., Raghavendra, A., Forte, V., Chin, S. F., Bardwell, H., Provenzano, E., Caldas, C., Lang, J., West, R., Tripathy, D., Press, M. F., Curtis, C. 2019; 10 (1): 2433

    Abstract

    The original version of this Article omitted from the Author Contributions statement that 'R.S. and J.G.R contributed equally to this work.' This has been corrected in both the PDF and HTML versions of the Article.

    View details for DOI 10.1038/s41467-019-10456-x

    View details for PubMedID 31147552

  • Spatial integration of radiology and pathology images to characterize breast cancer aggressiveness on pre-surgical MRI Rusu, M., Daniel, B., West, R., Angelini, E. D., Landman, B. A. SPIE-INT SOC OPTICAL ENGINEERING. 2019

    View details for DOI 10.1117/12.2512670

    View details for Web of Science ID 000483012700032

  • Framework for the co-registration of MRI and Histology Images in Prostate Cancer Patients with Radical Prostatectomy Rusu, M., Kunder, C., Fan, R., Ghanouni, P., West, R., Sonn, G., Brooks, J., Angelini, E. D., Landman, B. A. SPIE-INT SOC OPTICAL ENGINEERING. 2019

    View details for DOI 10.1117/12.2513099

    View details for Web of Science ID 000483012700057

  • Cell cycle progression in confining microenvironments is regulated by a growth-responsive TRPV4-PI3K/Akt-p27Kip1 signaling axis. Science advances Nam, S., Gupta, V. K., Lee, H. P., Lee, J. Y., Wisdom, K. M., Varma, S., Flaum, E. M., Davis, C., West, R. B., Chaudhuri, O. 2019; 5 (8): eaaw6171

    Abstract

    In tissues, cells reside in confining microenvironments, which may mechanically restrict the ability of a cell to double in size as it prepares to divide. How confinement affects cell cycle progression remains unclear. We show that cells progressed through the cell cycle and proliferated when cultured in hydrogels exhibiting fast stress relaxation but were mostly arrested in the G0/G1 phase of the cell cycle when cultured in hydrogels that exhibit slow stress relaxation. In fast-relaxing gels, activity of stretch-activated channels (SACs), including TRPV4, promotes activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which in turn drives cytoplasmic localization of the cell cycle inhibitor p27Kip1, thereby allowing S phase entry and proliferation. Cell growth during G1 activated the TRPV4-PI3K/Akt-p27Kip1 signaling axis, but growth is inhibited in the confining slow-relaxing hydrogels. Thus, in confining microenvironments, cells sense when growth is sufficient for division to proceed through a growth-responsive signaling axis mediated by SACs.

    View details for DOI 10.1126/sciadv.aaw6171

    View details for PubMedID 31457089

    View details for PubMedCentralID PMC6685709

  • Genomic landscape of ductal carcinoma in situ and association with progression. Breast cancer research and treatment Lin, C. Y., Vennam, S., Purington, N., Lin, E., Varma, S., Han, S., Desa, M., Seto, T., Wang, N. J., Stehr, H., Troxell, M. L., Kurian, A. W., West, R. B. 2019

    Abstract

    The detection rate of breast ductal carcinoma in situ (DCIS) has increased significantly, raising the concern that DCIS is overdiagnosed and overtreated. Therefore, there is an unmet clinical need to better predict the risk of progression among DCIS patients. Our hypothesis is that by combining molecular signatures with clinicopathologic features, we can elucidate the biology of breast cancer progression, and risk-stratify patients with DCIS.Targeted exon sequencing with a custom panel of 223 genes/regions was performed for 125 DCIS cases. Among them, 60 were from cases having concurrent or subsequent invasive breast cancer (IBC) (DCIS + IBC group), and 65 from cases with no IBC development over a median follow-up of 13 years (DCIS-only group). Copy number alterations in chromosome 1q32, 8q24, and 11q13 were analyzed using fluorescence in situ hybridization (FISH). Multivariable logistic regression models were fit to the outcome of DCIS progression to IBC as functions of demographic and clinical features.We observed recurrent variants of known IBC-related mutations, and the most commonly mutated genes in DCIS were PIK3CA (34.4%) and TP53 (18.4%). There was an inverse association between PIK3CA kinase domain mutations and progression (Odds Ratio [OR] 10.2, p < 0.05). Copy number variations in 1q32 and 8q24 were associated with progression (OR 9.3 and 46, respectively; both p < 0.05).PIK3CA kinase domain mutations and the absence of copy number gains in DCIS are protective against progression to IBC. These results may guide efforts to distinguish low-risk from high-risk DCIS.

    View details for DOI 10.1007/s10549-019-05401-x

    View details for PubMedID 31420779

  • Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy. Nature communications Caswell-Jin, J. L., McNamara, K., Reiter, J. G., Sun, R., Hu, Z., Ma, Z., Ding, J., Suarez, C. J., Tilk, S., Raghavendra, A., Forte, V., Chin, S. F., Bardwell, H., Provenzano, E., Caldas, C., Lang, J., West, R., Tripathy, D., Press, M. F., Curtis, C. 2019; 10 (1): 657

    Abstract

    Genomic changes observed across treatment may result from either clonal evolution or geographically disparate sampling of heterogeneous tumors. Here we use computational modeling based on analysis of fifteen primary breast tumors and find that apparent clonal change between two tumor samples can frequently be explained by pre-treatment heterogeneity, such that at least two regions are necessary to detect treatment-induced clonal shifts. To assess for clonal replacement, we devise a summary statistic based on whole-exome sequencing of a pre-treatment biopsy and multi-region sampling of the post-treatment surgical specimen and apply this measure to five breast tumors treated with neoadjuvant HER2-targeted therapy. Two tumors underwent clonal replacement with treatment, and mathematical modeling indicates these two tumors had resistant subclones prior to treatment and rates of resistance-related genomic changes that were substantially larger than previous estimates. Our results provide a needed framework to incorporate primary tumor heterogeneity in investigating the evolution of resistance.

    View details for PubMedID 30737380

  • Genomic analysis of benign prostatic hyperplasia implicates cellular re-landscaping in disease pathogenesis. JCI insight Middleton, L. W., Shen, Z., Varma, S., Pollack, A. S., Gong, X., Zhu, S., Zhu, C., Foley, J. W., Vennam, S., Sweeney, R. T., Tu, K., Biscocho, J., Eminaga, O., Nolley, R., Tibshirani, R., Brooks, J. D., West, R. B., Pollack, J. R. 2019; 5

    Abstract

    Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptoms in men. Current treatments target prostate physiology rather than BPH pathophysiology and are only partially effective. Here, we applied next-generation sequencing to gain new insight into BPH. By RNAseq, we uncovered transcriptional heterogeneity among BPH cases, where a 65-gene BPH stromal signature correlated with symptom severity. Stromal signaling molecules BMP5 and CXCL13 were enriched in BPH while estrogen regulated pathways were depleted. Notably, BMP5 addition to cultured prostatic myofibroblasts altered their expression profile towards a BPH profile that included the BPH stromal signature. RNAseq also suggested an altered cellular milieu in BPH, which we verified by immunohistochemistry and single-cell RNAseq. In particular, BPH tissues exhibited enrichment of myofibroblast subsets, whilst depletion of neuroendocrine cells and an estrogen receptor (ESR1)-positive fibroblast cell type residing near epithelium. By whole-exome sequencing, we uncovered somatic single-nucleotide variants (SNVs) in BPH, of uncertain pathogenic significance but indicative of clonal cell expansions. Thus, genomic characterization of BPH has identified a clinically-relevant stromal signature and new candidate disease pathways (including a likely role for BMP5 signaling), and reveals BPH to be not merely a hyperplasia, but rather a fundamental re-landscaping of cell types.

    View details for DOI 10.1172/jci.insight.129749

    View details for PubMedID 31094703

  • Increased Galectin-1 Expression in Thymic Epithelial Tumors. Clinical lung cancer Riess, J. W., Kong, C. S., West, R. B., Padda, S. K., Neal, J. W., Wakelee, H. A., Le, Q. 2018

    Abstract

    INTRODUCTION: Thymic epithelial tumors (TET) are rare malignancies with a paucity of data on biology and therapeutics. Galectin-1 is a member of the beta-galactoside binding protein family and has been shown to mediate tumor growth via modulation of immune cell function. This study examined galectin-1 expression in TET.PATIENTS AND METHODS: A tissue microarray of 68 patients with TET and 8 benign thymus controls were stained for galectin-1 expression and scored by a pathologist blinded to patient clinical and pathologic data. Galectin-1 expression+1 or greater staining intensity was considered positive. Clinical and pathologic data were abstracted from institutional databases. Expression of galectin-1 in thymic tumor was compared to benign thymus controls and correlated with pertinent clinical and pathologic data.RESULTS: Galectin-1 expression was higher in TET compared to benign thymus controls (65% vs. 0%). No significant association between galectin-1 expression and the development of recurrent disease, paraneoplastic syndromes, or overall survival was noted.CONCLUSION: Galectin-1 is overexpressed in the majority of TET. Detection of galectin-1 may differentiate benign from neoplastic thymic processes. Additional studies are needed to assess the role of galectin-1 in the development of TET.

    View details for PubMedID 30773448

  • The HTN3-MSANTD3 Fusion Gene Defines a Subset of Acinic Cell Carcinoma of the Salivary Gland. The American journal of surgical pathology Andreasen, S., Varma, S., Barasch, N., Thompson, L. D., Miettinen, M., Rooper, L., Stelow, E. B., Agander, T. K., Seethala, R. R., Chiosea, S. I., Homoe, P., Wessel, I., Larsen, S. R., Erentaite, D., Bishop, J. A., Ulhoi, B. P., Kiss, K., Melchior, L. C., Pollack, J. R., West, R. B. 2018

    Abstract

    The spectrum of tumors arising in the salivary glands is wide and has recently been shown to harbor a network of tumor-specific fusion genes. Acinic cell carcinoma (AciCC) is one of the more frequently encountered types of salivary gland carcinoma, but it has remained a genetic orphan until recently when a fusion between the HTN3 and MSANTD3 genes was described in one case. Neither of these 2 genes is known to be implicated in any other malignancy. This study was undertaken to investigate whether the HTN3-MSANTD3 fusion is a recurrent genetic event in AciCC and whether it is a characteristic of one of its histological variants. Of the 273 AciCCs screened, 9 cases showed rearrangement of MSANTD3 by break-apart fluorescence in situ hybridization, 2 had 1 to 2 extra signals, and 1 had gain, giving a total of 4.4% with MSANTD3 aberrations. In 6 of 7 available cases with MSANTD3 rearrangement, the HTN3-MSANTD3 fusion transcript was demonstrated with real-time polymerase chain reaction . Histologically, all fusion-positive cases were predominantly composed of serous tumor cells growing in solid sheets, with serous tumor cells expressing DOG-1 and the intercalated duct-like cell component being CK7 positive and S-100 positive in 6/9 cases. All but one case arose in the parotid gland, and none of the patients experienced a recurrence during follow-up. In contrast, the case with MSANTD3 gain metastasized to the cervical lymph nodes and lungs. In conclusion, we find the HTN3-MSANTD3 gene fusion to be a recurrent event in AciCC with prominent serous differentiation and an indolent clinical course.

    View details for PubMedID 30520817

  • Matrix mechanical plasticity regulates cancer cell migration through confining microenvironments. Nature communications Wisdom, K. M., Adebowale, K., Chang, J., Lee, J. Y., Nam, S., Desai, R., Rossen, N. S., Rafat, M., West, R. B., Hodgson, L., Chaudhuri, O. 2018; 9 (1): 4144

    Abstract

    Studies of cancer cell migration have found two modes: one that is protease-independent, requiring micron-sized pores or channels for cells to squeeze through, and one that is protease-dependent, relevant for confining nanoporous matrices such as basement membranes (BMs). However, many extracellular matrices exhibit viscoelasticity and mechanical plasticity, irreversibly deforming in response to force, so that pore size may be malleable. Here we report the impact of matrix plasticity on migration. We develop nanoporous and BM ligand-presenting interpenetrating network (IPN) hydrogels in which plasticity could be modulated independent of stiffness. Strikingly, cells in high plasticity IPNs carry out protease-independent migration through the IPNs. Mechanistically, cells in high plasticity IPNs extend invadopodia protrusions to mechanically and plastically open up micron-sized channels and then migrate through them. These findings uncover a new mode of protease-independent migration, in which cells can migrate through confining matrix if it exhibits sufficient mechanical plasticity.

    View details for PubMedID 30297715

  • A Structured Tumor-Immune Microenvironment in Triple Negative Breast Cancer Revealed by Multiplexed Ion Beam Imaging. Cell Keren, L., Bosse, M., Marquez, D., Angoshtari, R., Jain, S., Varma, S., Yang, S., Kurian, A., Van Valen, D., West, R., Bendall, S. C., Angelo, M. 2018; 174 (6): 1373

    Abstract

    The immune system is critical in modulating cancer progression, but knowledge of immune composition, phenotype, and interactions with tumor is limited. We used multiplexed ion beam imaging by time-of-flight (MIBI-TOF) to simultaneously quantify in situ expression of 36 proteins covering identity, function, and immune regulation at sub-cellular resolution in 41 triple-negative breast cancer patients. Multi-step processing, including deep-learning-based segmentation, revealed variability in the composition of tumor-immune populations across individuals, reconciled by overall immune infiltration and enriched co-occurrence of immune subpopulations and checkpoint expression. Spatial enrichment analysis showed immune mixed and compartmentalized tumors, coinciding with expression of PD1, PD-L1, and IDO in a cell-type- and location-specific manner. Ordered immune structures along the tumor-immune border were associated with compartmentalization and linked to survival. These data demonstrate organization in the tumor-immune microenvironment that is structured in cellular composition, spatial arrangement, and regulatory-protein expression and provide a framework to apply multiplexed imaging to immune oncology.

    View details for PubMedID 30193111

  • A Structured Tumor-Immune Microenvironment in Triple Negative Breast Cancer Revealed by Multiplexed Ion Beam Imaging CELL Keren, L., Bosse, M., Marquez, D., Angoshtari, R., Jain, S., Varma, S., Yang, S., Kurian, A., Van Valen, D., West, R., Bendall, S. C., Angelo, M. 2018; 174 (6): 1373-+
  • VISTA immune checkpoint deregulation in human triple-negative breast cancer Gruber, J. J., Juntilla, M. M., Yang, S., Geller, B., Jager, N., Lin, C., Lipchik, A. M., Chen, J., Ram, A., Vinayak, S., Telli, M. L., West, R. B., Ford, J. M., Snyder, M. P. AMER ASSOC CANCER RESEARCH. 2018
  • p300 and STAT3 drive YAP-independent mechanotransduction during breast cancer invasion Lee, J. Y., Chang, J., Nam, S., Lee, H., Dominguez, A. A., Varma, S., Qi, L. S., West, R. B., Chaudhuri, O. AMER ASSOC CANCER RESEARCH. 2018
  • Biological subtypes of nasopharyngeal carcinoma by genomic profiling Tay, K., Zhu, C., Vennam, S., Varma, S., Quynh-Thu Le, Sunwoo, J., West, R. AMER ASSOC CANCER RESEARCH. 2018
  • GFPT2-expressing cancer-associated fibroblasts mediate metabolic reprogramming in human lung adenocarcinoma. Cancer research Zhang, W., Bouchard, G., Yu, A., Shafiq, M., Jamali, M., Shrager, J. B., Ayers, K., Bakr, S., Gentles, A. J., Diehn, M., Quon, A., West, R. B., Nair, V., van de Rijn, M., Napel, S., Plevritis, S. K. 2018

    Abstract

    Metabolic reprogramming of the tumor microenvironment is recognized as a cancer hallmark. To identify new molecular processes associated with tumor metabolism, we analyzed the transcriptome of bulk and flow-sorted human primary non-small cell lung cancer (NSCLC) together with 18FDG-positron emission tomography scans, which provide a clinical measure of glucose uptake. Tumors with higher glucose uptake were functionally enriched for molecular processes associated with invasion in adenocarcinoma (AD) and cell growth in squamous cell carcinoma (SCC). Next, we identified genes correlated to glucose uptake that were predominately overexpressed in a single cell-type comprising the tumor microenvironment. For SCC, most of these genes were expressed by malignant cells, whereas in AD they were predominately expressed by stromal cells, particularly cancer-associated fibroblasts (CAFs). Among these AD genes correlated to glucose uptake, we focused on Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2), which codes for the Glutamine-Fructose-6-Phosphate Aminotransferase 2 (GFAT2), a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which is responsible for glycosylation. GFPT2 was predictive of glucose uptake independent of GLUT1, the primary glucose transporter, and was prognostically significant at both gene and protein level. We confirmed that normal fibroblasts transformed to CAF-like cells, following TGF-beta treatment, upregulated HBP genes, including GFPT2, with less change in genes driving glycolysis, pentose phosphate pathway and TCA cycle. Our work provides new evidence of histology-specific tumor-stromal properties associated with glucose uptake in NSCLC and identifies GFPT2 as a critical regulator of tumor metabolic reprogramming in AD.

    View details for PubMedID 29760045

  • Gene Expression in Nasopharyngeal Carcinoma by Laser Capture Microdissected Transcriptome Sequencing Tay, J. K., Zhu, C., Sunwoo, J., Le, Q. T., West, R. B. ELSEVIER SCIENCE INC. 2018: 1385
  • Pathologic Features and Clinical Outcomes of Breast Cancers with HER2/CEP17 ratio < 2.0 and mean HER2 signals /cell > 6.0 by FISH; A Multi-Institutional Study Ballard, M., Toukatly, M., Bean, G., Jalikis, F., Krings, G., Schmidt, R., Chen, Y., Rendi, M., Dintzis, S., Troxell, M., West, R., Sibley, R., Allison, K. NATURE PUBLISHING GROUP. 2018: 48
  • Recurrent MSANTD3 Aberrations Defines a Subset of Acinic Cell Carcinomas of the Salivary Gland Andreasen, S., Varma, S., Melchior, L. C., Agander, T. K., Kiss, K., Wessel, I., Homoe, P., Bishop, J., Pollack, J., West, R. NATURE PUBLISHING GROUP. 2018: 470–71
  • Potential Impact of Proposed HER2 FISH Guideline Updates on FISH results; A Multi-Institutional Study Ballard, M., MacKerricher, W., Jalikis, F., Krings, G., Schmidt, R., Chen, Y., Rendi, M., Dintzis, S., Troxell, M., West, R., Sibley, R., Allison, K. NATURE PUBLISHING GROUP. 2018: 48
  • Pathologic Features and Clinical Outcomes of HER2 FISH Cases with HER2: CEP17 ratio > 2.0 but < 4 HER2 signals/cell; A Multi-Institutional Study Ballard, M., Toukatly, M., Bean, G., Jalikis, F., Krings, G., Schmidt, R., Chen, Y., Dintzis, S., Troxell, M., West, R., Sibley, R., Allison, K. NATURE PUBLISHING GROUP. 2018: 47–48
  • Higher Absolute Lymphocyte Counts Predict Lower Mortality from Early-Stage Triple-Negative Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research Afghahi, A., Purington, N., Han, S. S., Desai, M., Pierson, E., Mathur, M. B., Seto, T., Thompson, C. A., Rigdon, J., Telli, M. L., Badve, S. S., Curtis, C., West, R. B., Horst, K., Gomez, S. L., Ford, J. M., Sledge, G. W., Kurian, A. W. 2018

    Abstract

    Tumor-infiltrating lymphocytes (TILs) in pre-treatment biopsies are associated with improved survival in triple-negative breast cancer (TNBC). We investigated whether higher peripheral lymphocyte counts are associated with lower breast cancer-specific mortality (BCM) and overall mortality (OM) in TNBC.Data on treatments and diagnostic tests from electronic medical records of two healthcare systems were linked with demographic, clinical, pathologic, and mortality data from the California Cancer Registry. Multivariable regression models adjusted for age, race/ethnicity, socioeconomic status, cancer stage, grade, neoadjuvant/adjuvant chemotherapy use, radiotherapy use, and germline BRCA1/2 mutations were used to evaluate associations between absolute lymphocyte count (ALC), BCM and OM. For a subgroup with TILs data available, we explored the relationship between TILs and peripheral lymphocyte counts.1,463 Stage I-III TNBC patients were diagnosed from 2000-2014; 1113 (76%) received neoadjuvant/adjuvant chemotherapy within one year of diagnosis. Of 759 patients with available ALC data, 481 (63.4%) were ever lymphopenic (minimum ALC <1.0 K/μL). On multivariable analysis, higher minimum ALC, but not absolute neutrophil count, predicted lower OM (hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.16-0.35) and BCM (HR: 0.19, CI: 0.11-0.34). Five-year probability of BCM was 15% for patients who were ever lymphopenic versus 4% for those who were not. An exploratory analysis (N=70) showed a significant association between TILs and higher peripheral lymphocyte counts during neoadjuvant chemotherapy.Higher peripheral lymphocyte counts predicted lower mortality from early-stage, potentially curable TNBC, suggesting that immune function may enhance the effectiveness of early TNBC treatment.

    View details for PubMedID 29581131

  • QUANTIFYING CHROMOSOMAL COPY NUMBER ALTERATIONS IN BREAST DUCTAL CARCINOMA IN SITU: A DEEP LEARNING BASED APPROACH Sirinukunwattana, K., Lin, J., Lu, P., Beca, F., Peng, J., Tolwani, A., Stancu, A., Varma, S., West, R., IEEE IEEE. 2018: 186–90
  • Genome-wide reconstruction of complex structural variants using read clouds NATURE METHODS Spies, N., Weng, Z., Bishara, A., McDaniel, J., Catoe, D., Zook, J. M., Salit, M., West, R. B., Batzoglou, S., Sidow, A. 2017; 14 (9): 915-+

    Abstract

    In read cloud approaches, microfluidic partitioning of long genomic DNA fragments and barcoding of shorter fragments derived from these fragments retains long-range information in short sequencing reads. This combination of short reads with long-range information represents a powerful alternative to single-molecule long-read sequencing. We develop Genome-wide Reconstruction of Complex Structural Variants (GROC-SVs) for SV detection and assembly from read cloud data and apply this method to Illumina-sequenced 10x Genomics sarcoma and breast cancer data sets. Compared with short-fragment sequencing, GROC-SVs substantially improves the specificity of breakpoint detection at comparable sensitivity. This approach also performs sequence assembly across multiple breakpoints simultaneously, enabling the reconstruction of events exhibiting remarkable complexity. We show that chromothriptic rearrangements occurred before copy number amplifications, and that rates of single-nucleotide variants and SVs are not correlated. Our results support the use of read cloud approaches to advance the characterization of large and complex structural variation.

    View details for PubMedID 28714986

  • Circulating Tumor DNA Detects Residual Disease and Anticipates Tumor Progression Earlier Than CT Imaging Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H., Azad, T. D., Zhou, L., Liu, C., Scherer, F., Kurtz, D. M., Esfahani, M. S., Say, C., Carter, J. N., Merriott, D., Dudley, J., Binkley, M. S., Modlin, L., Padda, S. K., Gensheimer, M., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Billy, W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: E4
  • 'Non-classical' HER2 FISH results in breast cancer: a multi-institutional study MODERN PATHOLOGY Ballard, M., Jalikis, F., Krings, G., Schmidt, R. A., Chen, Y., Rendi, M. H., Dintzis, S. M., Jensen, K. C., West, R. B., Sibley, R. K., Troxell, M. L., Allison, K. H. 2017; 30 (2): 227-235

    Abstract

    The 2013 CAP/ASCO HER2 Testing Guidelines Update modified HER2 FISH categories such that some cases with 'monosomy', 'co-amplification/polysomy', low-level increased HER2 signals or clustered heterogeneity now are considered amplified or equivocal. This study examines the frequency and clinico-pathologic characteristics of breast cancers with equivocal or 'non-classical' HER2 FISH results. Breast cancers (2001-2014) with HER2 FISH results, HER2 immunohistochemistry, ER, grade, and age from three institutions (Stanford, UCSF, UWMC) were collected. HER2 FISH was interpreted using the updated recommendations. Amplified cases with non-classical results were grouped into the following categories: (1) 'monosomy' (ratio ≥2.0, mean HER2/cell<4.0); (2) 'co-amplified' (ratio<2.0, mean HER2/cell ≥6.0); (3) 'low amplified' (ratio ≥2.0, mean HER2/cell 4.0-5.9). Heterogeneous cases with clustered HER2-positive cells were also included. Of 8068 cases, 5.2% were equivocal and 4.6% had a 'non-classical' HER2 amplified result; 1.4% 'monosomy', 0.8% 'co-amplified', 2.1% 'low amplified', and 0.3% clustered heterogeneity. These cancers had a high frequency of ER positive (80.4%), Nottingham grade 3 (52.1%) results. The highest percentage of grade 3 cancers (66.7%) and positive HER2 immunohistochemistry (31.7%) was in the 'co-amplified' group. The 'monosomy' group had the highest percent grade 1 cancers (13.3%) and was most frequently HER2 immunohistochemistry negative (30.1%). Equivocal cases had very similar characteristics to the 'low-amplified' category. Cases with non-classical HER2 amplification or equivocal results are typically ER positive, higher grade cancers. 'Co-amplified' cases have the highest frequencies of aggressive characteristics and 'monosomy' cases the highest frequencies of lower risk features. With little clinical outcomes data currently available on these non-classical HER2 results, these results support the current classification scheme for HER2 FISH, with case-by-case correlation with additional clinical-pathologic factors when evaluating whether to offer HER2-targeted therapies in these non-classical cases.Modern Pathology advance online publication, 14 October 2016; doi:10.1038/modpathol.2016.175.

    View details for DOI 10.1038/modpathol.2016.175

    View details for Web of Science ID 000393257400007

  • Loss of MAdCAM-1 Expression in Colorectal Adenocarcinoma Devereaux, K., Gomez, A., Varma, S., Pai, R., Modiano, N., Longacre, T., West, R., Troxell, M. NATURE PUBLISHING GROUP. 2017: 170A
  • Loss of MAdCAM-1 Expression in Colorectal Adenocarcinoma Devereaux, K., Gomez, A., Varma, S., Pai, R., Modiano, N., Longacre, T., West, R., Troxell, M. NATURE PUBLISHING GROUP. 2017: 170A
  • Fibroepithelial Lesions of the Breast Involved by Atypical Epithelial Proliferations: A 12-Year Single Institution Study Singer, B., Lin, C., West, R. NATURE PUBLISHING GROUP. 2017: 71A
  • Fibroepithelial Lesions of the Breast Involved by Atypical Epithelial Proliferations: A 12-Year Single Institution Study Singer, B., Lin, C., West, R. NATURE PUBLISHING GROUP. 2017: 71A
  • Recurrent rearrangements of the Myb/SANT-like DNA-binding domain containing 3 gene (MSANTD3) in salivary gland acinic cell carcinoma. PloS one Barasch, N., Gong, X., Kwei, K. A., Varma, S., Biscocho, J., Qu, K., Xiao, N., Lipsick, J. S., Pelham, R. J., West, R. B., Pollack, J. R. 2017; 12 (2)

    Abstract

    Pathogenic gene fusions have been identified in several histologic types of salivary gland neoplasia, but not previously in acinic cell carcinoma (AcCC). To discover novel gene fusions, we performed whole-transcriptome sequencing surveys of three AcCC archival cases. In one specimen we identified a novel HTN3-MSANTD3 gene fusion, and in another a novel PRB3-ZNF217 gene fusion. The structure of both fusions was consistent with the promoter of the 5' partner (HTN3 or PRB3), both highly expressed salivary gland genes, driving overexpression of full-length MSANTD3 or ZNF217. By fluorescence in situ hybridization of an expanded AcCC case series, we observed MSANTD3 rearrangements altogether in 3 of 20 evaluable cases (15%), but found no additional ZNF217 rearrangements. MSANTD3 encodes a previously uncharacterized Myb/SANT domain-containing protein. Immunohistochemical staining demonstrated diffuse nuclear MSANTD3 expression in 8 of 27 AcCC cases (30%), including the three cases with MSANTD3 rearrangement. MSANTD3 displayed heterogeneous expression in normal salivary ductal epithelium, as well as among other histologic types of salivary gland cancer though without evidence of translocation. In a broader survey, MSANTD3 showed variable expression across a wide range of normal and neoplastic human tissue specimens. In preliminary functional studies, engineered MSANTD3 overexpression in rodent salivary gland epithelial cells did not enhance cell proliferation, but led to significant upregulation of gene sets involved in protein synthesis. Our findings newly identify MSANTD3 rearrangement as a recurrent event in salivary gland AcCC, providing new insight into disease pathogenesis, and identifying a putative novel human oncogene.

    View details for DOI 10.1371/journal.pone.0171265

    View details for PubMedID 28212443

  • Local estrogen axis in the human bone microenvironment regulates estrogen receptor-positive breast cancer cells. Breast cancer research : BCR Amanatullah, D. F., Tamaresis, J. S., Chu, P., Bachmann, M. H., Hoang, N. M., Collyar, D., Mayer, A. T., West, R. B., Maloney, W. J., Contag, C. H., King, B. L. 2017; 19 (1): 121

    Abstract

    Approximately 70% of all breast cancers express the estrogen receptor, and are regulated by estrogen. While the ovaries are the primary source of estrogen in premenopausal women, most breast cancer is diagnosed following menopause, when systemic levels of this hormone decline. Estrogen production from androgen precursors is catalyzed by the aromatase enzyme. Although aromatase expression and local estrogen production in breast adipose tissue have been implicated in the development of primary breast cancer, the source of estrogen involved in the regulation of estrogen receptor-positive (ER+) metastatic breast cancer progression is less clear.Bone is the most common distant site of breast cancer metastasis, particularly for ER+ breast cancers. We employed a co-culture model using trabecular  bone tissues obtained from total hip replacement (THR) surgery specimens to study ER+ and estrogen receptor-negative (ER-) breast cancer cells within the human bone microenvironment. Luciferase-expressing ER+ (MCF-7, T-47D, ZR-75) and ER- (SK-BR-3, MDA-MB-231, MCF-10A) breast cancer cells were cultured directly on bone tissue fragments or in bone tissue-conditioned media, and monitored over time with bioluminescence imaging (BLI). Bone tissue-conditioned media were generated in the presence vs. absence of aromatase inhibitors, and testosterone. Bone tissue fragments were analyzed for aromatase expression by immunohistochemistry.ER+ breast cancer cells were preferentially sustained in co-cultures with bone tissues and bone tissue-conditioned media relative to ER- cells. Bone fragments analyzed by immunohistochemistry revealed expression of the aromatase enzyme. Bone tissue-conditioned media generated in the presence of testosterone had increased estrogen levels and heightened capacity to stimulate ER+ breast cancer cell proliferation. Pretreatment of cultured bone tissues with aromatase inhibitors, which inhibited estrogen production, reduced the capacity of conditioned media to stimulate ER+ cell proliferation.These results suggest that a local estrogen signaling axis regulates ER+ breast cancer cell viability and proliferation within the bone metastatic niche, and that aromatase inhibitors modulate this axis. Although endocrine therapies are highly effective in the treatment of ER+ breast cancer, resistance to these treatments reduces their efficacy. Characterization of estrogen signaling networks within the bone microenvironment will identify new strategies for combating metastatic progression and endocrine resistance.

    View details for PubMedID 29141657

    View details for PubMedCentralID PMC5688761

  • YAP-independent mechanotransduction drives breast cancer invasion. Lee, J. Y., Chang, J., Nam, S., Lee, H., Dominguez, A., Varma, S., Qi, L. S., West, R., Chaudhuri, O. AMER SOC CELL BIOLOGY. 2017
  • YAP-independent mechanotransduction drives breast cancer invasion. Lee, J. Y., Chang, J., Nam, S., Lee, H., Dominguez, A., Varma, S., Qi, L. S., West, R., Chaudhuri, O. AMER SOC CELL BIOLOGY. 2017
  • Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer discovery Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H., Azad, T. D., Khodadoust, M. S., Esfahani, M. S., Liu, C. L., Zhou, L., Scherer, F., Kurtz, D. M., Say, C., Carter, J. N., Merriott, D. J., Dudley, J. C., Binkley, M. S., Modlin, L., Padda, S. K., Gensheimer, M. F., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A. A., Diehn, M. 2017

    Abstract

    Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here we apply Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first post-treatment blood sample, indicating reliable identification of MRD. Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.

    View details for PubMedID 28899864

  • Circulating Tumor DNA Detects Minimal Residual Disease and Predicts Outcome in Localized Lung Cancer Chaudhuri, A., Lovejoy, A., Chabon, J., Newman, A., Stehr, H., Say, C., Carter, J., Zhou, L., West, R., Shrager, J., Neal, J., Wakelee, H., Loo, B., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S445
  • Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance CANCER DISCOVERY Jeong, Y., Hoang, N. T., Lovejoy, A., Stehr, H., Newman, A. M., Gentles, A. J., Kong, W., Diana Truong, D., Martin, S., Chaudhuri, A., Heiser, D., Zhou, L., Say, C., Carter, J. N., Hiniker, S. M., Loo, B. W., West, R. B., Beachy, P., Alizadeh, A. A., Diehn, M. 2017; 7 (1): 86-101

    Abstract

    Lung squamous cell carcinoma (LSCC) pathogenesis remains incompletely understood, and biomarkers predicting treatment response remain lacking. Here, we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histologic and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model. Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT). KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in patients with non-small lung cancer (NSCLC) and could be noninvasively identified in circulating tumor DNA. Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs.We developed an LSCC mouse model involving Trp53 and Keap1, which are frequently mutated in human LSCCs. In this model, ABSCs are the cell of origin of these tumors. KEAP1/NRF2 mutations increase radioresistance and predict local tumor recurrence in radiotherapy patients. Our findings are of potential clinical relevance and could lead to personalized treatment strategies for tumors with KEAP1/NRF2 mutations. Cancer Discov; 7(1); 86-101. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1.

    View details for DOI 10.1158/2159-8290.CD-16-0127

    View details for Web of Science ID 000396017700024

    View details for PubMedCentralID PMC5222718

  • Loss of Expression of AZGP1 Is Associated With Worse Clinical Outcomes in a Multi-Institutional Radical Prostatectomy Cohort. Prostate Brooks, J. D., Wei, W., Pollack, J. R., West, R. B., Shin, J. H., Sunwoo, J. B., Hawley, S. J., Auman, H., Newcomb, L. F., Simko, J., Hurtado-Coll, A., Troyer, D. A., Carroll, P. R., Gleave, M. E., Lin, D. W., Nelson, P. S., Thompson, I. M., True, L. D., McKenney, J. K., Feng, Z., Fazli, L. 2016; 76 (15): 1409-1419

    Abstract

    Given the uncertainties inherent in clinical measures of prostate cancer aggressiveness, clinically validated tissue biomarkers are needed. We tested whether Alpha-2-Glycoprotein 1, Zinc-Binding (AZGP1) protein levels, measured by immunohistochemistry, and RNA expression, by RNA in situ hybridization (RISH), predict recurrence after radical prostatectomy independent of clinical and pathological parameters.AZGP1 IHC and RISH were performed on a large multi-institutional tissue microarray resource including 1,275 men with 5 year median follow-up. The relationship between IHC and RISH expression levels was assessed using the Kappa analysis. Associations with clinical and pathological parameters were tested by the Chi-square test and the Wilcoxon rank sum test. Relationships with outcome were assessed with univariable and multivariable Cox proportional hazards models and the Log-rank test.Absent or weak expression of AZGP1 protein was associated with worse recurrence free survival (RFS), disease specific survival, and overall survival after radical prostatectomy in univariable analysis. AZGP1 protein expression, along with pre-operative serum PSA levels, surgical margin status, seminal vesicle invasion, extracapsular extension, and Gleason score predicted RFS on multivariable analysis. Similarly, absent or low AZGP1 RNA expression by RISH predicted worse RFS after prostatectomy in univariable and multivariable analysis.In our large, rigorously designed validation cohort, loss of AZGP1 expression predicts RFS after radical prostatectomy independent of clinical and pathological variables. Prostate © 2016 Wiley Periodicals, Inc.

    View details for DOI 10.1002/pros.23225

    View details for PubMedID 27325561

  • 'Non-classical' HER2 FISH results in breast cancer: a multi-institutional study. Modern pathology Ballard, M., Jalikis, F., Krings, G., Schmidt, R. A., Chen, Y., Rendi, M. H., Dintzis, S. M., Jensen, K. C., West, R. B., Sibley, R. K., Troxell, M. L., Allison, K. H. 2016

    Abstract

    The 2013 CAP/ASCO HER2 Testing Guidelines Update modified HER2 FISH categories such that some cases with 'monosomy', 'co-amplification/polysomy', low-level increased HER2 signals or clustered heterogeneity now are considered amplified or equivocal. This study examines the frequency and clinico-pathologic characteristics of breast cancers with equivocal or 'non-classical' HER2 FISH results. Breast cancers (2001-2014) with HER2 FISH results, HER2 immunohistochemistry, ER, grade, and age from three institutions (Stanford, UCSF, UWMC) were collected. HER2 FISH was interpreted using the updated recommendations. Amplified cases with non-classical results were grouped into the following categories: (1) 'monosomy' (ratio ≥2.0, mean HER2/cell<4.0); (2) 'co-amplified' (ratio<2.0, mean HER2/cell ≥6.0); (3) 'low amplified' (ratio ≥2.0, mean HER2/cell 4.0-5.9). Heterogeneous cases with clustered HER2-positive cells were also included. Of 8068 cases, 5.2% were equivocal and 4.6% had a 'non-classical' HER2 amplified result; 1.4% 'monosomy', 0.8% 'co-amplified', 2.1% 'low amplified', and 0.3% clustered heterogeneity. These cancers had a high frequency of ER positive (80.4%), Nottingham grade 3 (52.1%) results. The highest percentage of grade 3 cancers (66.7%) and positive HER2 immunohistochemistry (31.7%) was in the 'co-amplified' group. The 'monosomy' group had the highest percent grade 1 cancers (13.3%) and was most frequently HER2 immunohistochemistry negative (30.1%). Equivocal cases had very similar characteristics to the 'low-amplified' category. Cases with non-classical HER2 amplification or equivocal results are typically ER positive, higher grade cancers. 'Co-amplified' cases have the highest frequencies of aggressive characteristics and 'monosomy' cases the highest frequencies of lower risk features. With little clinical outcomes data currently available on these non-classical HER2 results, these results support the current classification scheme for HER2 FISH, with case-by-case correlation with additional clinical-pathologic factors when evaluating whether to offer HER2-targeted therapies in these non-classical cases.Modern Pathology advance online publication, 14 October 2016; doi:10.1038/modpathol.2016.175.

    View details for DOI 10.1038/modpathol.2016.175

    View details for PubMedID 27739440

  • CAPP-Seq Circulating Tumor DNA Analysis for Early Detection of Tumor Progression After Definitive Radiation Therapy for Lung Cancer Chaudhuri, A. A., Lovejoy, A. F., Chabon, J. J., Newman, A., Stehr, H., Say, C., Aggarwal, S., Carter, J. N., West, R. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2016: S41–S42
  • BRAF inhibitor therapy of primary ameloblastoma ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY Tan, S., Pollack, J. R., Kaplan, M. J., Colevas, A., West, R. B. 2016; 122 (4): 518–19

    View details for PubMedID 27651290

  • Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance. Cancer discovery Jeong, Y., Hoang, N. T., Lovejoy, A., Stehr, H., Newman, A. M., Gentles, A. J., Kong, W., Truong, D., Martin, S., Chaudhuri, A., Heiser, D., Zhou, L., Say, C., Carter, J. N., Hiniker, S. M., Loo, B. W., West, R. B., Beachy, P., Alizadeh, A. A., Diehn, M. 2016

    Abstract

    Lung squamous cell carcinoma (LSCC) pathogenesis remains incompletely understood, and biomarkers predicting treatment response remain lacking. Here, we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histologic and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model. Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT). KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in patients with non-small lung cancer (NSCLC) and could be noninvasively identified in circulating tumor DNA. Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs.We developed an LSCC mouse model involving Trp53 and Keap1, which are frequently mutated in human LSCCs. In this model, ABSCs are the cell of origin of these tumors. KEAP1/NRF2 mutations increase radioresistance and predict local tumor recurrence in radiotherapy patients. Our findings are of potential clinical relevance and could lead to personalized treatment strategies for tumors with KEAP1/NRF2 mutations. Cancer Discov; 7(1); 86-101. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1.

    View details for PubMedID 27663899

  • Ameloblastoma: a clinical review and trends in management EUROPEAN ARCHIVES OF OTO-RHINO-LARYNGOLOGY McClary, A. C., West, R. B., McClary, A. C., Pollack, J. R., Fischbein, N. J., Holsinger, C. F., Sunwoo, J., Colevas, A. D., Sirjani, D. 2016; 273 (7): 1649-1661

    Abstract

    Ameloblastoma is a rare odontogenic neoplasm of the mandible and maxilla, with multiple histologic variants, and high recurrence rates if improperly treated. The current mainstay of treatment is wide local excision with appropriate margins and immediate reconstruction. Here we review the ameloblastoma literature, using the available evidence to highlight the change in management over the past several decades. In addition, we explore the recent molecular characterization of these tumors which may point towards new potential avenues of personalized treatment.

    View details for DOI 10.1007/s00405-015-3631-8

    View details for PubMedID 25926124

  • BRAF inhibitor treatment of primary BRAF-mutant ameloblastoma with pathologic assessment of response ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY Tan, S., Pollack, J. R., Kaplan, M. J., Colevas, A. D., West, R. B. 2016; 122 (1): E5-E7

    Abstract

    Molecular characterization of ameloblastoma has indicated a high frequency of driver mutations in BRAF and SMO. Preclinical data suggest that Food and Drug Administration-approved BRAF-targeted therapies may be immediately relevant for patients with ameloblastoma positive for the BRAF V600E mutation.A neoadjuvant treatment regime of dabrafenib was given to a patient with recurrent BRAF-mutant mandibular ameloblastoma. The patient subsequently underwent left mandible composite resection of the tumor and pathologic evaluation of treatment response.The ameloblastoma had a slow but dramatic response with >90% tumor volume reduction. The inner areas of the tumor underwent degeneration and squamous differentiation, and intact ameloblastoma was present in the outer areas associated with bone.Targeted neoadjuvant therapy for ameloblastoma may be useful in certain clinical settings of primary ameloblastoma. These might include tumors of advanced local stage when a neoadjuvant reduction could alter the extent of surgery and instances of local recurrence when surgical options are limited.

    View details for DOI 10.1016/j.oooo.2015.12.016

    View details for Web of Science ID 000377426600002

    View details for PubMedID 27209484

  • Transcriptome sequencing analysis of four psammomatous meningiomas Samghabadi, P., Forgo, E., West, R., Vogel, H. LIPPINCOTT WILLIAMS & WILKINS. 2016: 575
  • Integrated digital error suppression for improved detection of circulating tumor DNA NATURE BIOTECHNOLOGY Newman, A. M., Lovejoy, A. F., Klass, D. M., Kurtz, D. M., Chabon, J. J., Scherer, F., Stehr, H., Liu, C. L., Bratman, S. V., Say, C., Zhou, L., Carter, J. N., West, R. B., Sledge, G. W., Shrager, J. B., Loo, B. W., Neal, J. W., Wakelee, H. A., Diehn, M., Alizadeh, A. A. 2016; 34 (5): 547-555

    Abstract

    High-throughput sequencing of circulating tumor DNA (ctDNA) promises to facilitate personalized cancer therapy. However, low quantities of cell-free DNA (cfDNA) in the blood and sequencing artifacts currently limit analytical sensitivity. To overcome these limitations, we introduce an approach for integrated digital error suppression (iDES). Our method combines in silico elimination of highly stereotypical background artifacts with a molecular barcoding strategy for the efficient recovery of cfDNA molecules. Individually, these two methods each improve the sensitivity of cancer personalized profiling by deep sequencing (CAPP-Seq) by about threefold, and synergize when combined to yield ∼15-fold improvements. As a result, iDES-enhanced CAPP-Seq facilitates noninvasive variant detection across hundreds of kilobases. Applied to non-small cell lung cancer (NSCLC) patients, our method enabled biopsy-free profiling of EGFR kinase domain mutations with 92% sensitivity and >99.99% specificity at the variant level, and with 90% sensitivity and 96% specificity at the patient level. In addition, our approach allowed monitoring of NSCLC ctDNA down to 4 in 10(5) cfDNA molecules. We anticipate that iDES will aid the noninvasive genotyping and detection of ctDNA in research and clinical settings.

    View details for DOI 10.1038/nbt.3520

    View details for PubMedID 27018799

  • Validation of Digital Whole Slide Imaging System for Breast Sentinel Lymph Node Touch Prep Analysis: A Single Institution Experience Hoffmann, J., McGinnis, L., Mafnas, C. T., Ziskin, J., Folkins, A. K., Allison, K., West, R. B., Higgins, J. P., Kambham, N., Long, S. R., Tan, B. NATURE PUBLISHING GROUP. 2016: 496A
  • HER2 FISH Equivocal Category: Does Retesting Resolve This Clinical Grey Zone? Ballard, M., Srivastava, S., West, R. B., Jensen, K. C., Sibley, R. K., Allison, K. NATURE PUBLISHING GROUP. 2016: 31A
  • Genomic Profiling of Ductal Carcinoma In Situ: Can We Predict Outcome? Lin, C., Vennam, S., Sweeney, R. T., Zhu, S. X., Varma, S., West, R. B. NATURE PUBLISHING GROUP. 2016: 54A
  • Correlation of Protein Expression with Chromosomal Copy Number Alterations in the Progression of Early Breast Neoplasia to DCIS Forgo, E., Varma, S., West, R. B. NATURE PUBLISHING GROUP. 2016: 41A
  • Genomic Profiling of Ductal Carcinoma In Situ: Can We Predict Outcome? Lin, C., Vennam, S., Sweeney, R. T., Zhu, S. X., Varma, S., West, R. B. NATURE PUBLISHING GROUP. 2016: 54A
  • Correlation of Protein Expression with Chromosomal Copy Number Alterations in the Progression of Early Breast Neoplasia to DCIS Forgo, E., Varma, S., West, R. B. NATURE PUBLISHING GROUP. 2016: 41A
  • Validation of Digital Whole Slide Imaging System for Intraoperative Breast Sentinel Lymph Node Touch Prep Analysis: A Single Institution Experience Hoffmann, J., McGinnis, L., Mafnas, C. T., Ziskin, J., Folkins, A. K., Allison, K., West, R. B., Higgins, J. P., Kambham, N., Long, S. R., Tan, B. NATURE PUBLISHING GROUP. 2016: 496A
  • The prognostic landscape of genes and infiltrating immune cells across human cancers Gentles, A. J., Newman, A. M., Liu, C., Bratman, S. V., Feng, W., Kim, D., Nair, V. S., Yue, X., Khuong, A., Hoang, C. D., Diehn, M., West, R. B., Plevritis, S. K., Alizadeh, A. A. AMER ASSOC CANCER RESEARCH. 2015
  • Read clouds uncover variation in complex regions of the human genome. Genome research Bishara, A., Liu, Y., Weng, Z., Kashef-Haghighi, D., Newburger, D. E., West, R., Sidow, A., Batzoglou, S. 2015; 25 (10): 1570-1580

    Abstract

    Although an increasing amount of human genetic variation is being identified and recorded, determining variants within repeated sequences of the human genome remains a challenge. Most population and genome-wide association studies have therefore been unable to consider variation in these regions. Core to the problem is the lack of a sequencing technology that produces reads with sufficient length and accuracy to enable unique mapping. Here, we present a novel methodology of using read clouds, obtained by accurate short-read sequencing of DNA derived from long fragment libraries, to confidently align short reads within repeat regions and enable accurate variant discovery. Our novel algorithm, Random Field Aligner (RFA), captures the relationships among the short reads governed by the long read process via a Markov Random Field. We utilized a modified version of the Illumina TruSeq synthetic long-read protocol, which yielded shallow-sequenced read clouds. We test RFA through extensive simulations and apply it to discover variants on the NA12878 human sample, for which shallow TruSeq read cloud sequencing data are available, and on an invasive breast carcinoma genome that we sequenced using the same method. We demonstrate that RFA facilitates accurate recovery of variation in 155 Mb of the human genome, including 94% of 67 Mb of segmental duplication sequence and 96% of 11 Mb of transcribed sequence, that are currently hidden from short-read technologies.

    View details for DOI 10.1101/gr.191189.115

    View details for PubMedID 26286554

    View details for PubMedCentralID PMC4579342

  • Integrating Tumor and Stromal Gene Expression Signatures With Clinical Indices for Survival Stratification of Early-Stage Non-Small Cell Lung Cancer. Journal of the National Cancer Institute Gentles, A. J., Bratman, S. V., Lee, L. J., Harris, J. P., Feng, W., Nair, R. V., Shultz, D. B., Nair, V. S., Hoang, C. D., West, R. B., Plevritis, S. K., Alizadeh, A. A., Diehn, M. 2015; 107 (10)

    Abstract

    Accurate survival stratification in early-stage non-small cell lung cancer (NSCLC) could inform the use of adjuvant therapy. We developed a clinically implementable mortality risk score incorporating distinct tumor microenvironmental gene expression signatures and clinical variables.Gene expression profiles from 1106 nonsquamous NSCLCs were used for generation and internal validation of a nine-gene molecular prognostic index (MPI). A quantitative polymerase chain reaction (qPCR) assay was developed and validated on an independent cohort of formalin-fixed paraffin-embedded (FFPE) tissues (n = 98). A prognostic score using clinical variables was generated using Surveillance, Epidemiology, and End Results data and combined with the MPI. All statistical tests for survival were two-sided.The MPI stratified stage I patients into prognostic categories in three microarray and one FFPE qPCR validation cohorts (HR = 2.99, 95% CI = 1.55 to 5.76, P < .001 in stage IA patients of the largest microarray validation cohort; HR = 3.95, 95% CI = 1.24 to 12.64, P = .01 in stage IA of the qPCR cohort). Prognostic genes were expressed in distinct tumor cell subpopulations, and genes implicated in proliferation and stem cells portended poor outcomes, while genes involved in normal lung differentiation and immune infiltration were associated with superior survival. Integrating the MPI with clinical variables conferred greatest prognostic power (HR = 3.43, 95% CI = 2.18 to 5.39, P < .001 in stage I patients of the largest microarray cohort; HR = 3.99, 95% CI = 1.67 to 9.56, P < .001 in stage I patients of the qPCR cohort). Finally, the MPI was prognostic irrespective of somatic alterations in EGFR, KRAS, TP53, and ALK.The MPI incorporates genes expressed in the tumor and its microenvironment and can be implemented clinically using qPCR assays on FFPE tissues. A composite model integrating the MPI with clinical variables provides the most accurate risk stratification.

    View details for DOI 10.1093/jnci/djv211

    View details for PubMedID 26286589

  • Integrating Tumor and Stromal Gene Expression Signatures With Clinical Indices for Survival Stratification of Early-Stage Non-Small Cell Lung Cancer. Journal of the National Cancer Institute Gentles, A. J., Bratman, S. V., Lee, L. J., Harris, J. P., Feng, W., Nair, R. V., Shultz, D. B., Nair, V. S., Hoang, C. D., West, R. B., Plevritis, S. K., Alizadeh, A. A., Diehn, M. 2015; 107 (10)

    Abstract

    Accurate survival stratification in early-stage non-small cell lung cancer (NSCLC) could inform the use of adjuvant therapy. We developed a clinically implementable mortality risk score incorporating distinct tumor microenvironmental gene expression signatures and clinical variables.Gene expression profiles from 1106 nonsquamous NSCLCs were used for generation and internal validation of a nine-gene molecular prognostic index (MPI). A quantitative polymerase chain reaction (qPCR) assay was developed and validated on an independent cohort of formalin-fixed paraffin-embedded (FFPE) tissues (n = 98). A prognostic score using clinical variables was generated using Surveillance, Epidemiology, and End Results data and combined with the MPI. All statistical tests for survival were two-sided.The MPI stratified stage I patients into prognostic categories in three microarray and one FFPE qPCR validation cohorts (HR = 2.99, 95% CI = 1.55 to 5.76, P < .001 in stage IA patients of the largest microarray validation cohort; HR = 3.95, 95% CI = 1.24 to 12.64, P = .01 in stage IA of the qPCR cohort). Prognostic genes were expressed in distinct tumor cell subpopulations, and genes implicated in proliferation and stem cells portended poor outcomes, while genes involved in normal lung differentiation and immune infiltration were associated with superior survival. Integrating the MPI with clinical variables conferred greatest prognostic power (HR = 3.43, 95% CI = 2.18 to 5.39, P < .001 in stage I patients of the largest microarray cohort; HR = 3.99, 95% CI = 1.67 to 9.56, P < .001 in stage I patients of the qPCR cohort). Finally, the MPI was prognostic irrespective of somatic alterations in EGFR, KRAS, TP53, and ALK.The MPI incorporates genes expressed in the tumor and its microenvironment and can be implemented clinically using qPCR assays on FFPE tissues. A composite model integrating the MPI with clinical variables provides the most accurate risk stratification.

    View details for DOI 10.1093/jnci/djv211

    View details for PubMedID 26286589

  • Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer BREAST CANCER RESEARCH Afghahi, A., Forgo, E., Mitani, A. A., Desai, M., Varma, S., Seto, T., Rigdon, J., Jensen, K. C., Troxell, M. L., Gomez, S. L., Das, A. K., Beck, A. H., Kurian, A. W., West, R. B. 2015; 17

    Abstract

    Screening mammography has contributed to a significant increase in the diagnosis of ductal carcinoma in situ (DCIS), raising concerns about overdiagnosis and overtreatment. Building on prior observations from lineage evolution analysis, we examined whether measuring genomic features of DCIS would predict association with invasive breast carcinoma (IBC). The long-term goal is to enhance standard clinicopathologic measures of low- versus high-risk DCIS and to enable risk-appropriate treatment.We studied three common chromosomal copy number alterations (CNA) in IBC and designed fluorescence in situ hybridization-based assay to measure copy number at these loci in DCIS samples. Clinicopathologic data were extracted from the electronic medical records of Stanford Cancer Institute and linked to demographic data from the population-based California Cancer Registry; results were integrated with data from tissue microarrays of specimens containing DCIS that did not develop IBC versus DCIS with concurrent IBC. Multivariable logistic regression analysis was performed to describe associations of CNAs with these two groups of DCIS.We examined 271 patients with DCIS (120 that did not develop IBC and 151 with concurrent IBC) for the presence of 1q, 8q24 and 11q13 copy number gains. Compared to DCIS-only patients, patients with concurrent IBC had higher frequencies of CNAs in their DCIS samples. On multivariable analysis with conventional clinicopathologic features, the copy number gains were significantly associated with concurrent IBC. The state of two of the three copy number gains in DCIS was associated with a risk of IBC that was 9.07 times that of no copy number gains, and the presence of gains at all three genomic loci in DCIS was associated with a more than 17-fold risk (P = 0.0013).CNAs have the potential to improve the identification of high-risk DCIS, defined by presence of concurrent IBC. Expanding and validating this approach in both additional cross-sectional and longitudinal cohorts may enable improved risk stratification and risk-appropriate treatment in DCIS.

    View details for DOI 10.1186/s13058-015-0623-y

    View details for Web of Science ID 000359348400001

    View details for PubMedID 26265211

    View details for PubMedCentralID PMC4534146

  • The prognostic landscape of genes and infiltrating immune cells across human cancers NATURE MEDICINE Gentles, A. J., Newman, A. M., Liu, C. L., Bratman, S. V., Feng, W., Kim, D., Nair, V. S., Xu, Y., Khuong, A., Hoang, C. D., Diehn, M., West, R. B., Plevritis, S. K., Alizadeh, A. A. 2015; 21 (8): 938-945

    Abstract

    Molecular profiles of tumors and tumor-associated cells hold great promise as biomarkers of clinical outcomes. However, existing data sets are fragmented and difficult to analyze systematically. Here we present a pan-cancer resource and meta-analysis of expression signatures from ∼18,000 human tumors with overall survival outcomes across 39 malignancies. By using this resource, we identified a forkhead box MI (FOXM1) regulatory network as a major predictor of adverse outcomes, and we found that expression of favorably prognostic genes, including KLRB1 (encoding CD161), largely reflect tumor-associated leukocytes. By applying CIBERSORT, a computational approach for inferring leukocyte representation in bulk tumor transcriptomes, we identified complex associations between 22 distinct leukocyte subsets and cancer survival. For example, tumor-associated neutrophil and plasma cell signatures emerged as significant but opposite predictors of survival for diverse solid tumors, including breast and lung adenocarcinomas. This resource and associated analytical tools (http://precog.stanford.edu) may help delineate prognostic genes and leukocyte subsets within and across cancers, shed light on the impact of tumor heterogeneity on cancer outcomes, and facilitate the discovery of biomarkers and therapeutic targets.

    View details for DOI 10.1038/nm.3909

    View details for PubMedID 26193342

  • Clinically Relevant Molecular Subtypes in Leiomyosarcoma. Clinical cancer research Guo, X., Jo, V. Y., Mills, A. M., Zhu, S. X., Lee, C., Espinosa, I., Nucci, M. R., Varma, S., Forgó, E., Hastie, T., Anderson, S., Ganjoo, K., Beck, A. H., West, R. B., Fletcher, C. D., van de Rijn, M. 2015; 21 (15): 3501-3511

    Abstract

    Leiomyosarcoma is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for leiomyosarcoma. Recognition of different molecular subtypes is necessary to evaluate novel therapeutic options. In a previous study on 51 leiomyosarcomas, we identified three molecular subtypes in leiomyosarcoma. The current study was performed to determine whether the existence of these subtypes could be confirmed in independent cohorts.Ninety-nine cases of leiomyosarcoma were expression profiled with 3'end RNA-Sequencing (3SEQ). Consensus clustering was conducted to determine the optimal number of subtypes.We identified 3 leiomyosarcoma molecular subtypes and confirmed this finding by analyzing publically available data on 82 leiomyosarcoma from The Cancer Genome Atlas (TCGA). We identified two new formalin-fixed, paraffin-embedded tissue-compatible diagnostic immunohistochemical markers; LMOD1 for subtype I leiomyosarcoma and ARL4C for subtype II leiomyosarcoma. A leiomyosarcoma tissue microarray with known clinical outcome was used to show that subtype I leiomyosarcoma is associated with good outcome in extrauterine leiomyosarcoma while subtype II leiomyosarcoma is associated with poor prognosis in both uterine and extrauterine leiomyosarcoma. The leiomyosarcoma subtypes showed significant differences in expression levels for genes for which novel targeted therapies are being developed, suggesting that leiomyosarcoma subtypes may respond differentially to these targeted therapies.We confirm the existence of 3 molecular subtypes in leiomyosarcoma using two independent datasets and show that the different molecular subtypes are associated with distinct clinical outcomes. The findings offer an opportunity for treating leiomyosarcoma in a subtype-specific targeted approach. Clin Cancer Res; 21(15); 3501-11. ©2015 AACR.

    View details for DOI 10.1158/1078-0432.CCR-14-3141

    View details for PubMedID 25896974

  • Automated Analysis and Classification of Histological Tissue Features by Multi-Dimensional Microscopic Molecular Profiling PLOS ONE Riordan, D. P., Varma, S., West, R. B., Brown, P. O. 2015; 10 (7)

    Abstract

    Characterization of the molecular attributes and spatial arrangements of cells and features within complex human tissues provides a critical basis for understanding processes involved in development and disease. Moreover, the ability to automate steps in the analysis and interpretation of histological images that currently require manual inspection by pathologists could revolutionize medical diagnostics. Toward this end, we developed a new imaging approach called multidimensional microscopic molecular profiling (MMMP) that can measure several independent molecular properties in situ at subcellular resolution for the same tissue specimen. MMMP involves repeated cycles of antibody or histochemical staining, imaging, and signal removal, which ultimately can generate information analogous to a multidimensional flow cytometry analysis on intact tissue sections. We performed a MMMP analysis on a tissue microarray containing a diverse set of 102 human tissues using a panel of 15 informative antibody and 5 histochemical stains plus DAPI. Large-scale unsupervised analysis of MMMP data, and visualization of the resulting classifications, identified molecular profiles that were associated with functional tissue features. We then directly annotated H&E images from this MMMP series such that canonical histological features of interest (e.g. blood vessels, epithelium, red blood cells) were individually labeled. By integrating image annotation data, we identified molecular signatures that were associated with specific histological annotations and we developed statistical models for automatically classifying these features. The classification accuracy for automated histology labeling was objectively evaluated using a cross-validation strategy, and significant accuracy (with a median per-pixel rate of 77% per feature from 15 annotated samples) for de novo feature prediction was obtained. These results suggest that high-dimensional profiling may advance the development of computer-based systems for automatically parsing relevant histological and cellular features from molecular imaging data of arbitrary human tissue samples, and can provide a framework and resource to spur the optimization of these technologies.

    View details for DOI 10.1371/journal.pone.0128975

    View details for Web of Science ID 000358197600010

    View details for PubMedCentralID PMC4503351

  • Cell-lineage heterogeneity and driver mutation recurrence in pre-invasive breast neoplasia GENOME MEDICINE Weng, Z., Spies, N., Zhu, S. X., Newburger, D. E., Kashef-Haghighi, D., Batzoglou, S., Sidow, A., West, R. B. 2015; 7

    Abstract

    All cells in an individual are related to one another by a bifurcating lineage tree, in which each node is an ancestral cell that divided into two, each branch connects two nodes, and the root is the zygote. When a somatic mutation occurs in an ancestral cell, all its descendants carry the mutation, which can then serve as a lineage marker for the phylogenetic reconstruction of tumor progression. Using this concept, we investigate cell lineage relationships and genetic heterogeneity of pre-invasive neoplasias compared to invasive carcinomas.We deeply sequenced over a thousand phylogenetically informative somatic variants in 66 morphologically independent samples from six patients that represent a spectrum of normal, early neoplasia, carcinoma in situ, and invasive carcinoma. For each patient, we obtained a highly resolved lineage tree that establishes the phylogenetic relationships among the pre-invasive lesions and with the invasive carcinoma.The trees reveal lineage heterogeneity of pre-invasive lesions, both within the same lesion, and between histologically similar ones. On the basis of the lineage trees, we identified a large number of independent recurrences of PIK3CA H1047 mutations in separate lesions in four of the six patients, often separate from the diagnostic carcinoma.Our analyses demonstrate that multi-sample phylogenetic inference provides insights on the origin of driver mutations, lineage heterogeneity of neoplastic proliferations, and the relationship of genomically aberrant neoplasias with the primary tumors. PIK3CA driver mutations may be comparatively benign inducers of cellular proliferation.

    View details for DOI 10.1186/s13073-015-0146-2

    View details for Web of Science ID 000353532600001

    View details for PubMedID 25918554

    View details for PubMedCentralID PMC4410742

  • Diffuse High Intensity PD-L1 Staining in Thymic Epithelial Tumors. Journal of thoracic oncology Padda, S. K., Riess, J. W., Schwartz, E. J., Tian, L., Kohrt, H. E., Neal, J. W., West, R. B., Wakelee, H. A. 2015; 10 (3): 500-508

    Abstract

    Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has well-established clinical activity across many tumor types. PD-L1 protein expression by immunohistochemistry is emerging as a predictive biomarker of response to these therapies. Here, we examine PD-L1 expression in a thymic epithelial tumor (TET) tissue microarray (TMA).The TMA contained 69 TETs and 17 thymic controls, with each case represented by triplicate cores. The TMA was stained with rabbit monoclonal antibody (clone 15; Sino Biological, Beijing, China) to human PD-L1. PD-L1 staining was scored based on intensity as follows: 0 = none, 1 = equivocal/uninterpretable, 2 = weak, and 3 = intermediate-strong. Those cases with all cores scoring three in the epithelial component were categorized as PD-L1 and the remaining as PD-L1.PD-L1 scores were more frequent in TETs than in controls (68.1% versus 17.6%; p = 0.0036). PD-L1 scores and histology were significantly correlated, with higher intensity staining in World Health Organization (WHO). B2/B3/C TETs. Only 14.8% of TETs had PD-L1 staining of associated lymphocytes. In an adjusted analysis (age/sex), PD-L1 TETs had a significantly worse overall survival (hazard ratio: 5.40, 95% confidence interval: 1.13-25.89; p = 0.035) and a trend for worse event-free survival (hazard ratio: 2.94, 95% confidence interval: 0.94-9.24; p = 0.064).PD-L1 expression was present in all cases of TETs within the epithelial component but only in a minority in the lymphocytic component. TETs stained more intensely for PD-L1 than in controls, and PD-L1 TETs were associated with more aggressive histology and worse prognosis. This study lends rationale to a clinical trial with anti-PD-1/PD-L1 therapy in this rare tumor type.

    View details for DOI 10.1097/JTO.0000000000000429

    View details for PubMedID 25402569

  • Novel mutations in neuroendocrine carcinoma of the breast: possible therapeutic targets. Applied immunohistochemistry & molecular morphology Ang, D., Ballard, M., Beadling, C., Warrick, A., Schilling, A., O'Gara, R., Pukay, M., Neff, T. L., West, R. B., Corless, C. L., Troxell, M. L. 2015; 23 (2): 97-103

    Abstract

    Primary neuroendocrine carcinoma of the breast is a rare variant, accounting for only 2% to 5% of diagnosed breast cancers, and may have relatively aggressive behavior. Mutational profiling of invasive ductal breast cancers has yielded potential targets for directed cancer therapy, yet most studies have not included neuroendocrine carcinomas. In a tissue microarray screen, we found a 2.4% prevalence (9/372) of neuroendocrine breast carcinoma, including several with lobular morphology. We then screened primary or metastatic neuroendocrine breast carcinomas (excluding papillary and mucinous) for mutations in common cancer genes using polymerase chain reaction-mass spectroscopy (643 hotspot mutations across 53 genes), or semiconductor-based next-generation sequencing analysis (37 genes). Mutations were identified in 5 of 15 tumors, including 3 with PIK3CA exon 9 E542K mutations, 2 of which also harbored point mutations in FGFR family members (FGFR1 P126S, FGFR4 V550M). Single mutations were found in each of KDR (A1065T) and HRAS (G12A). PIK3CA mutations are common in other types of breast carcinoma. However, FGFR and RAS family mutations are exceedingly rare in the breast cancer literature. Likewise, activating mutations in the receptor tyrosine kinase KDR (VEGFR2) have been reported in angiosarcomas and non-small cell lung cancers; the KDR A1065T mutation is reported to be sensitive to VEGFR kinase inhibitors, and fibroblast growth factor receptor inhibitors are in trials. Our findings demonstrate the utility of broad-based genotyping in the study of rare tumors such as neuroendocrine breast cancer.

    View details for DOI 10.1097/PDM.0b013e3182a40fd1

    View details for PubMedID 25679062

  • Translocation and Expression of MSANTD3 in Neoplasia and Normal Tissue Barasch, N., Xue, G., Sweeney, R., Varma, S., Biscocho, J., Kwei, K., Pelham, R., Lipsick, J., West, R., Pollack, J. NATURE PUBLISHING GROUP. 2015: 320A
  • Translocation and Expression of MSANTD3 in Neoplasia and Normal Tissue Barasch, N., Xue, G., Sweeney, R., Varma, S., Biscocho, J., Kwei, K., Pelham, R., Lipsick, J., West, R., Pollack, J. NATURE PUBLISHING GROUP. 2015: 320A
  • Survey of SMO and BRAF Mutational Status in Head and Neck and Adnexal Neoplasms McClary, A., Biscocho, J., Varma, S., Pollack, J., West, R. NATURE PUBLISHING GROUP. 2015: 327A–328A
  • Correlation of Protein Expression With Chromosomal Copy Number Alterations for Risk Classification of Ductal Carcinoma In Situ Forgo, E., Varma, S., West, R. NATURE PUBLISHING GROUP. 2015: 45A
  • Characterization of Breast Cancers With Equivocal and Non-Classical HER2 FISH Results - A Multi-Institutional Study Ballard, M., Jalikis, F., Krings, G., Schmidt, R., Chen, Y., Rendi, M., Dintzis, S. M., Jensen, K., West, R., Sibley, R., Allison, K. NATURE PUBLISHING GROUP. 2015: 35A
  • Genomic Profiling of Radial Scar Lin, C., Sweeney, R., Zhu, S., West, R. NATURE PUBLISHING GROUP. 2015: 54A
  • Correlation of Protein Expression With Chromosomal Copy Number Alterations for Risk Classification of Ductal Carcinoma In Situ Forgo, E., Varma, S., West, R. NATURE PUBLISHING GROUP. 2015: 45A
  • Genomic Profiling of Radial Scar Lin, C., Sweeney, R., Zhu, S., West, R. NATURE PUBLISHING GROUP. 2015: 54A
  • Survey of SMO and BRAF Mutational Status in Head and Neck and Adnexal Neoplasms McClaty, A., Biscocho, J., Varma, S., Pollacic, J., West, R. NATURE PUBLISHING GROUP. 2015: 327A–328A
  • GLI1, CTNNB1 and NOTCH1 Protein Expression in a Thymic Epithelial Malignancy Tissue Microarray. Anticancer research Riess, J. W., West, R., Dean, M., Klimowicz, A. C., Neal, J. W., Hoang, C., Wakelee, H. A. 2015; 35 (2): 669-676

    Abstract

    Thymic epithelial tumors (TET) are rare. Wingless and INT (WNT), NOTCH and sonic hedgehog pathway interactions between thymocytes and thymic stroma are important to thymus and T-cell development. We analyzed a thymoma tissue microarray (TMA) for glioma associated oncogene homolog 1 (GLI1), NOTCH1 and catenin (cadherin-associated protein, beta 1) (CTNNB1) expression as surrogate markers of sonic hedgehog, NOTCH and WNT pathway activity.GLI1, NOTCH1 and CTNNB1 expression were assayed in a tissue microarray of 68 TET and eight benign thymus by fluorescent immunohistochemistry (AQUA) as surrogates for activity of the sonic hedgehog, NOTCH and WNT pathways respectively.No difference in tumor GLI1 (mean 201 vs. 211, p=0.31), CTNNB1 (mean 222 vs. 306, p=0.66) or NOTCH1 expression (mean 317 vs. 325, p=0.82) was noted between thymic tumor and benign thymus.No evidence for preferential expression of GLI1, NOTCH1 or CTNNB1 was noted. High-throughput immunofluorescence using AQUA technology can help overcome limitations of small sample size and tissue heterogeneity when analyzing protein expression in thymic tumors.

    View details for PubMedID 25667444

  • Novel mutations in neuroendocrine carcinoma of the breast: possible therapeutic targets. Applied immunohistochemistry & molecular morphology Ang, D., Ballard, M., Beadling, C., Warrick, A., Schilling, A., O'Gara, R., Pukay, M., Neff, T. L., West, R. B., Corless, C. L., Troxell, M. L. 2015; 23 (2): 97-103

    Abstract

    Primary neuroendocrine carcinoma of the breast is a rare variant, accounting for only 2% to 5% of diagnosed breast cancers, and may have relatively aggressive behavior. Mutational profiling of invasive ductal breast cancers has yielded potential targets for directed cancer therapy, yet most studies have not included neuroendocrine carcinomas. In a tissue microarray screen, we found a 2.4% prevalence (9/372) of neuroendocrine breast carcinoma, including several with lobular morphology. We then screened primary or metastatic neuroendocrine breast carcinomas (excluding papillary and mucinous) for mutations in common cancer genes using polymerase chain reaction-mass spectroscopy (643 hotspot mutations across 53 genes), or semiconductor-based next-generation sequencing analysis (37 genes). Mutations were identified in 5 of 15 tumors, including 3 with PIK3CA exon 9 E542K mutations, 2 of which also harbored point mutations in FGFR family members (FGFR1 P126S, FGFR4 V550M). Single mutations were found in each of KDR (A1065T) and HRAS (G12A). PIK3CA mutations are common in other types of breast carcinoma. However, FGFR and RAS family mutations are exceedingly rare in the breast cancer literature. Likewise, activating mutations in the receptor tyrosine kinase KDR (VEGFR2) have been reported in angiosarcomas and non-small cell lung cancers; the KDR A1065T mutation is reported to be sensitive to VEGFR kinase inhibitors, and fibroblast growth factor receptor inhibitors are in trials. Our findings demonstrate the utility of broad-based genotyping in the study of rare tumors such as neuroendocrine breast cancer.

    View details for DOI 10.1097/PDM.0b013e3182a40fd1

    View details for PubMedID 25679062

  • GLI1, CTNNB1 and NOTCH1 protein expression in a thymic epithelial malignancy tissue microarray. Anticancer research Riess, J. W., West, R., Dean, M., Klimowicz, A. C., Neal, J. W., Hoang, C., Wakelee, H. A. 2015; 35 (2): 669-676

    Abstract

    Thymic epithelial tumors (TET) are rare. Wingless and INT (WNT), NOTCH and sonic hedgehog pathway interactions between thymocytes and thymic stroma are important to thymus and T-cell development. We analyzed a thymoma tissue microarray (TMA) for glioma associated oncogene homolog 1 (GLI1), NOTCH1 and catenin (cadherin-associated protein, beta 1) (CTNNB1) expression as surrogate markers of sonic hedgehog, NOTCH and WNT pathway activity.GLI1, NOTCH1 and CTNNB1 expression were assayed in a tissue microarray of 68 TET and eight benign thymus by fluorescent immunohistochemistry (AQUA) as surrogates for activity of the sonic hedgehog, NOTCH and WNT pathways respectively.No difference in tumor GLI1 (mean 201 vs. 211, p=0.31), CTNNB1 (mean 222 vs. 306, p=0.66) or NOTCH1 expression (mean 317 vs. 325, p=0.82) was noted between thymic tumor and benign thymus.No evidence for preferential expression of GLI1, NOTCH1 or CTNNB1 was noted. High-throughput immunofluorescence using AQUA technology can help overcome limitations of small sample size and tissue heterogeneity when analyzing protein expression in thymic tumors.

    View details for PubMedID 25667444

  • Pemetrexed in patients with thymic malignancies previously treated with chemotherapy. Lung cancer Liang, Y., Padda, S. K., Riess, J. W., West, R. B., Neal, J. W., Wakelee, H. A. 2015; 87 (1): 34-38

    Abstract

    Thymic malignancies are rare, with limited published trials of chemotherapy activity. We performed a retrospective analysis of pemetrexed activity in patients with thymic malignancies.Patients with unresectable histologically confirmed invasive, recurrent, or metastatic thymoma or thymic carcinoma seen at the Stanford Cancer Center between January 2005 and November 2013 were identified, and those who were treated with pemetrexed in the second-line setting and beyond were included in this analysis.A total of 81 thymic malignancy patients were identified, of whom 16 received pemetrexed alone (N=14) or in combination (N=2). There were 10 patients (62.5%) with thymic carcinoma and 6 patients (37.5%) with thymoma. Among the 6 patients with thymoma, best response was 1 (17%) with a partial response (PR) and 5 (83%) with stable disease (SD). At a median follow-up of 21.2 months, the median PFS in the thymoma patients was 13.8 months (95% CI, 4.9-22.6 months) and the median OS was 20.1 months (95% CI, 16.4-23.9 months). Among the 10 patients with thymic carcinoma, best response to treatment was 1 (10%) PR, 5 (50%) SD, and 4 (40%) progressive disease (PD). At a median follow-up of 13.5 months, the median PFS in patients with thymic carcinoma was 6.5 months (95% CI, 0.2-12.8 months) and the median OS was 12.7 months (95% CI, 2.9-22.5 months).This small retrospective study demonstrates modest pemetrexed activity and disease stabilization in thymic malignancies with a clinically meaningful duration, and supports previous reports of pemetrexed efficacy in these rare diseases.

    View details for DOI 10.1016/j.lungcan.2014.11.006

    View details for PubMedID 25443273

  • Read Clouds Uncover Variation in Complex Regions of the Human Genome Bishara, A., Liu, Y., Kashef-Haghighi, D., Weng, Z., Newburger, D. E., West, R., Sidow, A., Batzoglou, S., Przytycka, T. M. SPRINGER-VERLAG BERLIN. 2015: 30–31
  • Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer. Breast cancer research Afghahi, A., Forgó, E., Mitani, A. A., Desai, M., Varma, S., Seto, T., Rigdon, J., Jensen, K. C., Troxell, M. L., Gomez, S. L., Das, A. K., Beck, A. H., Kurian, A. W., West, R. B. 2015; 17: 108-?

    Abstract

    Screening mammography has contributed to a significant increase in the diagnosis of ductal carcinoma in situ (DCIS), raising concerns about overdiagnosis and overtreatment. Building on prior observations from lineage evolution analysis, we examined whether measuring genomic features of DCIS would predict association with invasive breast carcinoma (IBC). The long-term goal is to enhance standard clinicopathologic measures of low- versus high-risk DCIS and to enable risk-appropriate treatment.We studied three common chromosomal copy number alterations (CNA) in IBC and designed fluorescence in situ hybridization-based assay to measure copy number at these loci in DCIS samples. Clinicopathologic data were extracted from the electronic medical records of Stanford Cancer Institute and linked to demographic data from the population-based California Cancer Registry; results were integrated with data from tissue microarrays of specimens containing DCIS that did not develop IBC versus DCIS with concurrent IBC. Multivariable logistic regression analysis was performed to describe associations of CNAs with these two groups of DCIS.We examined 271 patients with DCIS (120 that did not develop IBC and 151 with concurrent IBC) for the presence of 1q, 8q24 and 11q13 copy number gains. Compared to DCIS-only patients, patients with concurrent IBC had higher frequencies of CNAs in their DCIS samples. On multivariable analysis with conventional clinicopathologic features, the copy number gains were significantly associated with concurrent IBC. The state of two of the three copy number gains in DCIS was associated with a risk of IBC that was 9.07 times that of no copy number gains, and the presence of gains at all three genomic loci in DCIS was associated with a more than 17-fold risk (P = 0.0013).CNAs have the potential to improve the identification of high-risk DCIS, defined by presence of concurrent IBC. Expanding and validating this approach in both additional cross-sectional and longitudinal cohorts may enable improved risk stratification and risk-appropriate treatment in DCIS.

    View details for DOI 10.1186/s13058-015-0623-y

    View details for PubMedID 26265211

  • Automated Analysis and Classification of Histological Tissue Features by Multi-Dimensional Microscopic Molecular Profiling. PloS one Riordan, D. P., Varma, S., West, R. B., Brown, P. O. 2015; 10 (7)

    Abstract

    Characterization of the molecular attributes and spatial arrangements of cells and features within complex human tissues provides a critical basis for understanding processes involved in development and disease. Moreover, the ability to automate steps in the analysis and interpretation of histological images that currently require manual inspection by pathologists could revolutionize medical diagnostics. Toward this end, we developed a new imaging approach called multidimensional microscopic molecular profiling (MMMP) that can measure several independent molecular properties in situ at subcellular resolution for the same tissue specimen. MMMP involves repeated cycles of antibody or histochemical staining, imaging, and signal removal, which ultimately can generate information analogous to a multidimensional flow cytometry analysis on intact tissue sections. We performed a MMMP analysis on a tissue microarray containing a diverse set of 102 human tissues using a panel of 15 informative antibody and 5 histochemical stains plus DAPI. Large-scale unsupervised analysis of MMMP data, and visualization of the resulting classifications, identified molecular profiles that were associated with functional tissue features. We then directly annotated H&E images from this MMMP series such that canonical histological features of interest (e.g. blood vessels, epithelium, red blood cells) were individually labeled. By integrating image annotation data, we identified molecular signatures that were associated with specific histological annotations and we developed statistical models for automatically classifying these features. The classification accuracy for automated histology labeling was objectively evaluated using a cross-validation strategy, and significant accuracy (with a median per-pixel rate of 77% per feature from 15 annotated samples) for de novo feature prediction was obtained. These results suggest that high-dimensional profiling may advance the development of computer-based systems for automatically parsing relevant histological and cellular features from molecular imaging data of arbitrary human tissue samples, and can provide a framework and resource to spur the optimization of these technologies.

    View details for DOI 10.1371/journal.pone.0128975

    View details for PubMedID 26176839

    View details for PubMedCentralID PMC4503351

  • Cell-lineage heterogeneity and driver mutation recurrence in pre-invasive breast neoplasia. Genome medicine Weng, Z., Spies, N., Zhu, S. X., Newburger, D. E., Kashef-Haghighi, D., Batzoglou, S., Sidow, A., West, R. B. 2015; 7 (1): 28-?

    Abstract

    All cells in an individual are related to one another by a bifurcating lineage tree, in which each node is an ancestral cell that divided into two, each branch connects two nodes, and the root is the zygote. When a somatic mutation occurs in an ancestral cell, all its descendants carry the mutation, which can then serve as a lineage marker for the phylogenetic reconstruction of tumor progression. Using this concept, we investigate cell lineage relationships and genetic heterogeneity of pre-invasive neoplasias compared to invasive carcinomas.We deeply sequenced over a thousand phylogenetically informative somatic variants in 66 morphologically independent samples from six patients that represent a spectrum of normal, early neoplasia, carcinoma in situ, and invasive carcinoma. For each patient, we obtained a highly resolved lineage tree that establishes the phylogenetic relationships among the pre-invasive lesions and with the invasive carcinoma.The trees reveal lineage heterogeneity of pre-invasive lesions, both within the same lesion, and between histologically similar ones. On the basis of the lineage trees, we identified a large number of independent recurrences of PIK3CA H1047 mutations in separate lesions in four of the six patients, often separate from the diagnostic carcinoma.Our analyses demonstrate that multi-sample phylogenetic inference provides insights on the origin of driver mutations, lineage heterogeneity of neoplastic proliferations, and the relationship of genomically aberrant neoplasias with the primary tumors. PIK3CA driver mutations may be comparatively benign inducers of cellular proliferation.

    View details for DOI 10.1186/s13073-015-0146-2

    View details for PubMedID 25918554

    View details for PubMedCentralID PMC4410742

  • Fast and scalable inference of multi-sample cancer lineages. Genome biology Popic, V., Salari, R., Hajirasouliha, I., Kashef-Haghighi, D., West, R. B., Batzoglou, S. 2015; 16 (1): 91-?

    Abstract

    Somatic variants can be used as lineage markers for the phylogenetic reconstruction of cancer evolution. Since somatic phylogenetics is complicated by sample heterogeneity, novel specialized tree-building methods are required for cancer phylogeny reconstruction. We present LICHeE (Lineage Inference for Cancer Heterogeneity and Evolution), a novel method that automates the phylogenetic inference of cancer progression from multiple somatic samples. LICHeE uses variant allele frequencies of somatic single nucleotide variants obtained by deep sequencing to reconstruct multi-sample cell lineage trees and infer the subclonal composition of the samples. LICHeE is open source and available at http://viq854.github.io/lichee .

    View details for DOI 10.1186/s13059-015-0647-8

    View details for PubMedID 25944252

    View details for PubMedCentralID PMC4501097

  • Effects of Thrombopoietin Mimetics on Patients with Chronic ITP: Perspectives from Blood Transcriptome Profiling Analysis Zhang, H., Zhang, B., Guo, X., Haq, N., West, R. B., Bussel, J. B., Zehnder, J. L. AMER SOC HEMATOLOGY. 2014
  • Long noncoding RNA EWSAT1-mediated gene repression facilitates Ewing sarcoma oncogenesis JOURNAL OF CLINICAL INVESTIGATION Howarth, M. M., Simpson, D., Ngok, S. P., Nieves, B., Chen, R., Siprashvili, Z., Vaka, D., Breese, M. R., Crompton, B. D., Alexe, G., Hawkins, D. S., Jacobson, D., Brunner, A. L., West, R., Mora, J., Stegmaier, K., Khavari, P., Sweet-Cordero, E. A. 2014; 124 (12): 5275-5290

    Abstract

    Chromosomal translocation that results in fusion of the genes encoding RNA-binding protein EWS and transcription factor FLI1 (EWS-FLI1) is pathognomonic for Ewing sarcoma. EWS-FLI1 alters gene expression through mechanisms that are not completely understood. We performed RNA sequencing (RNAseq) analysis on primary pediatric human mesenchymal progenitor cells (pMPCs) expressing EWS-FLI1 in order to identify gene targets of this oncoprotein. We determined that long noncoding RNA-277 (Ewing sarcoma-associated transcript 1 [EWSAT1]) is upregulated by EWS-FLI1 in pMPCs. Inhibition of EWSAT1 expression diminished the ability of Ewing sarcoma cell lines to proliferate and form colonies in soft agar, whereas EWSAT1 inhibition had no effect on other cell types tested. Expression of EWS-FLI1 and EWSAT1 repressed gene expression, and a substantial fraction of targets that were repressed by EWS-FLI1 were also repressed by EWSAT1. Analysis of RNAseq data from primary human Ewing sarcoma further supported a role for EWSAT1 in mediating gene repression. We identified heterogeneous nuclear ribonucleoprotein (HNRNPK) as an RNA-binding protein that interacts with EWSAT1 and found a marked overlap in HNRNPK-repressed genes and those repressed by EWS-FLI1 and EWSAT1, suggesting that HNRNPK participates in EWSAT1-mediated gene repression. Together, our data reveal that EWSAT1 is a downstream target of EWS-FLI1 that facilitates the development of Ewing sarcoma via the repression of target genes.

    View details for DOI 10.1172/JC172124

    View details for Web of Science ID 000345677200020

    View details for PubMedID 25401475

  • Ameloblastoma driver mutations revealed by next-generation sequencing of formalin-fixed paraffin-embedded specimens McClary, A. C., Sweeney, R. T., Biscocho, J., Myers, B. R., Neahring, L., Kwei, K. A., Qu, K., Gong, X., Ng, T., Jones, C. D., Varma, S., Odegaard, J. I., Rubin, B., Troxell, M. L., Pelham, R. J., Zehnder, J. L., Beachy, P. A., Pollack, J. R., West, R. B. AMER ASSOC CANCER RESEARCH. 2014
  • PEMETREXED IN PATIENTS WITH THYMIC MALIGNANCIES PREVIOUSLY TREATED WITH CHEMOTHERAPY Liang, Y., Padda, S., Riess, J. W., West, R., Neal, J. W., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2014: S226

Publications

2018

Fernandez-Pol S, van de Rijn M, Natkunam Y, Charville GW. Immunohistochemistry for PAX7 is a useful confirmatory marker for Ewing sarcoma in decalcified bone marrow core biopsy specimens. Virchows Arch. 2018 Jul 17. doi: 10.1007/s00428-018-2410-5. PubMed PDF

Zhang W, Bouchard G , Yu A, Shafiq M, Jamali M, Shrager JB, Ayers K, Bakr S, Gentles AJ, Diehn M, Quon A, West RB, Nair V, van de Rijn , Napel S, Plevritis SK. GFPT2-expressing cancer-associated fibroblasts mediate metabolic reprogramming in human lung adenocarcinoma.Cancer Res. 2018 May 14. pii: canres.2928.2017. doi: 10.1158/0008-5472.CAN-17-2928. PubMed PDF

Afghahi A, Purington N, Han SS, Desai M, Pierson E, Mathur MB, Seto T, Thompson CA, Rigdon J, Telli ML, Badve SS, Curtis C, West RB, Horst K, Gomez SL, Ford JM, Sledge GW, Kurian AW. Higher Absolute Lymphocyte Counts Predict Lower Mortality from Early-Stage Triple-Negative Breast Cancer. Clin Cancer Res. 2018 Mar 26. pii: clincanres.1323.2017. doi: 10.1158/1078-0432.CCR-17-1323. PubMed PDF

Przybyl J, Kidzinski L, Hastie T, Debiec-Rychter M, Nusse R, van de Rijn M. Gene expression profiling of low-grade endometrial stromal sarcoma indicates fusion protein-mediated activation of the Wnt signaling pathway. Gynecol Oncol. 2018 Mar 12. pii: S0090-8258(18)30177-X. doi: 10.1016/j.ygyno.2018.03.007. PubMed PDF

Hayes MN, McCarthy K, Jin A, Oliveira ML, Iyer S, Garcia SP, Sindiri S, Gryder B, Motala Z, Nielsen GP, Borg JP, van de Rijn M, Malkin D, Khan J, Ignatius MS, Langenau DM. Vangl2/RhoA Signaling Pathway Regulates Stem Cell Self-Renewal Programs and Growth in Rhabdomyosarcoma. Cell Stem Cell. 2018 Mar 1;22(3):414-427.e6. doi: 10.1016/j.stem.2018.02.002. PubMed PDF

Joanna Przybyl, Jacob J. Chabon, Lien Spans, Kristen N. Ganjoo, Sujay Vennam, Aaron M. Newman, Erna Forgó, Sushama Varma, Shirley Zhu , Maria Debiec-Rychter, Ash A. Alizadeh, Maximilian Diehn, Matt van de Rijn. Combination approach for detecting different types of alterations in circulating tumor DNA in leiomyosarcoma. Clin Cancer Res. 2018 Feb 20. pii: clincanres.3704.2017. doi: 10.1158/1078-0432.CCR-17-3704. PubMed PDF

2017

Cancer Genome Atlas Research Network. National Cancer Institute at NIH.Collaborators (264) Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas. Cell. 2017 Nov 2;171(4):950-965.e28. doi: 10.1016/j PubMed PDF

Amanatullah DF, Tamaresis JS, Chu P, Bachmann MH, Hoang NM, Collyar D, Mayer AT, West RB, Maloney WJ, Contag CH, King BL. Local estrogen axis in the human bone microenvironment regulates estrogen receptor-positive breast cancer cells. Breast Cancer Res. 2017 Nov 15;19(1):121. doi: 10.1186/s13058-017-0910-x. PubMed PDF

Y.C.KO, C.ZHU, S.ZHU, S.VENNAMR, C.JORDANJ, POLLACK, R.WEST GENE EXPRESSION PROFILE OF AMELOBLASTOMA Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. Volume 124, Issue 3, September 2017, Page e204. PDF

Chaudhuri AA, Chabon JJ, Lovejoy AF, Newman AM, Stehr H, Azad TD, Khodadoust MS, Esfahani MS3, Liu CL, Zhou L, Scherer F, Kurtz DM, Say C, Carter JN, Merriott DJ, Dudley JC, Binkley MS, Modlin L, Padda SK, Gensheimer MF, West RB, Shrager JB, Neal JW, Wakelee HA, Loo BW, Alizadeh A4, Diehn M. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discov. 2017 Sep 12. pii: CD-17-0716. doi: 10.1158/2159-8290.CD-17-0716. PubMed PDF

Spies N, Weng Z, Bishara A, McDaniel J, Catoe D, Zook JM, Salit M, West RB, Batzoglou 4, Sidow A. Genome-wide reconstruction of complex structural variants using read clouds. Nat Methods. 2017 Jul 17. doi: 10.1038/nmeth.4366. PubMed PDF

Charville GW, Wang WL, Ingram DR, Roy A, Thomas D, Patel RM, Hornick JL, van de Rijn M, Lazar AJ. EWSR1 fusion proteins mediate PAX7 expression in Ewing sarcoma. Mod Pathol. 2017 Jun 23. doi: 10.1038/modpathol.2017.49. PubMed PDF

Przybyl J, Kowalewska M, Quattrone A, Dewaele B, Vanspauwen V, Varma S, Vennam , Newman AM, Swierniak M, Bakuła-Zalewska E, Siedlecki JA, Bidzinski M, Cools J, van de Rijn M, Debiec-Rychter M. Macrophage infiltration and genetic landscape of undifferentiated uterine sarcomas. JCI Insight. 2017 Jun 2;2(11). pii: 94033. doi: 10.1172/jci.insight.94033. PubMed PDF

Schaefer IM, Wang Y, Liang CW, Bahri N, Quattrone A, Doyle L, Mariño-Enríquez A, Lauria A, Zhu M, Debiec-Rychter M, Grunewald S, Hechtman JF, Dufresne A, Antonescu CR, Beadling C, Sicinska ET, van de Rijn M, Demetri GD, Ladanyi M, Corless CL, Heinrich MC, Raut CP, Bauer S, Fletcher JA. MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation. Nat Commun. 2017 Mar 8;8:14674. doi: 10.1038/ncomms14674.  PubMed   PDF

Ballard M, Jalikis F, Krings G, Schmidt RA, Chen YY, Rendi MH, Dintzis SM, Jensen KC,, West RB, Sibley RK, Troxell ML, Allison KH. 'Non-classical' HER2 FISH results in breast cancer: a multi-institutional study.  Mod Pathol. 2017 Feb;30(2):227-235. doi: 10.1038/modpathol.2016.175.  PubMed   PDF

Barasch N, Gong X, Kwei KA, Varma S, Biscocho J, Qu K, Xiao N, Lipsick JS, Pelham RJ, West RB, Pollack JR.. Recurrent rearrangements of the Myb/SANT-like DNA-binding domain containing 3 gene (MSANTD3) in salivary gland acinic cell carcinoma.   PLoS One. 2017 Feb 17; 12(2): e0171265.  PubMed   PDF

Jeong Y, Hoang NT, Lovejoy A, Stehr H, Newman AM, Gentles AJ, Kong W, Truong D, Martin S, Chaudhuri A, Heiser D, Zhou L, Say C, Carter JN, Hiniker SM, Loo BW Jr, West RB, Beachy P, Alizadeh AA, Diehn M. . Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance.   Cancer Discov. 2017 Jan;7(1):86-101. doi: 10.1158/2159-8290.CD-16-0127. PubMed   PDF

2016

Brooks JD, Wei W, Pollack JR, West RB, Shin JH, Sunwoo JB, Hawley SJ, Auman H, Newcomb LF, Simko J, Hurtado-Coll A, Troyer DA, Carroll PR, Gleave ME, Lin DW, Nelson PS, Thompson IM, True LD, McKenney JK, Feng Z, Fazli L. Loss of Expression of AZGP1 Is Associated With Worse Clinical Outcomes in a Multi-Institutional Radical Prostatectomy Cohort. Prostate. 2016 Nov;76(15):1409-19. doi: 10.1002/pros.23225. Epub 2016 Jun 21. PubMed  PDF

Choi HM, Calvert CR, Husain N, Huss D, Barsi JC, Deverman BE, Hunter RC, Kato M, Lee SM, Abelin AC, Rosenthal AZ, Akbari OS, Li Y, Hay BA, Sternberg PW, Patterson PH1, Davidson EH, Mazmanian SK, Prober DA, van de Rijn M, Leadbetter JR, Newman DK1, Readhead C, Bronner ME, Wold B, Lansford R, Sauka-Spengler T, Fraser SE, Pierce NA. Mapping a multiplexed zoo of mRNA expression.   Development. 2016 Oct 1;143(19):3632-3637. PubMed   PDF

Charville GW, Varma S, Forgó E, Dumont SN, Zambrano E, Trent JC, Lazar AJ, van de Rijn M. PAX7 Expression in Rhabdomyosarcoma, Related Soft Tissue Tumors, and Small Round Blue Cell Neoplasms. Am J Surg Pathol. 2016 Oct;40(10):1305-15. doi: 10.109  PubMed   PDF

Tan S, Pollack JR, Kaplan MJ, Colevas AD, West RB. BRAF inhibitor therapy of primary ameloblastoma.   Oral Surg Oral Med Oral Pathol Oral Radiol. 2016 Oct;122(4):518-9. doi: 10.1016/j.oooo.2016.05.017.  PubMed PDF

Weiskopf K, Jahchan NS, Schnorr PJ, Cristea S, Ring AM, Maute RL, Volkmer AK, Volkmer JP, Liu J, Lim JS, Yang D, Seitz G, Nguyen T, Wu D, Jude K, Guerston H, Barkal A, Trapani F, George J, Poirier JT, Gardner EE, Miles LA, de Stanchina E, Lofgren SM, Vogel H, Winslow MM, Dive C, Thomas RK, Rudin CM, van de Rijn M, Majeti R, Garcia KC, Weissman IL, Sage J.  CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J Clin Invest. 2016 Jun 13. pii: 81603. doi: 10.1172/JCI81603 PubMed   PDF 

Newman AM, Lovejoy AF, Klass DM, Kurtz DM, Chabon JJ, Scherer F, Stehr H, Liu CL, Bratman SV, Say C, Zhou L, Carter JN, West RB, Sledge GW Jr, Shrager JB, Loo BW Jr, Neal JW, Wakelee HA, Diehn M, Alizadeh AA.  Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol. 2016 May;34(5):547-55. doi: 10.1038/nbt.3520. Epub 2016 Mar 28. PubMed   PDF

Cleven AH, Sannaa GA, Briaire-de Bruijn I, Ingram DR, van de Rijn M, Rubin BP, de Vries MW, Watson KL, Torres KE, Wang WL, van Duinen SG, Hogendoorn PC, Lazar AJ, Bovée JV. Loss of H3K27 tri-methylation is a diagnostic marker for malignant peripheral nerve sheath tumors and an indicator for an inferior survival. Mod Pathol. 2016 Mar 18. doi: 10.1038/modpathol.2016.45. PubMed   PDF 

Tan S, Pollack JR, Kaplan MJ, Colevas AD, West RB. BRAF inhibitor treatment of primary BRAF-mutant ameloblastoma with pathologic assessment of response.   Oral Surg Oral Med Oral Pathol Oral Radiol. 2016 Feb 23. pii: S2212-4403(16)00064-X.  PubMed    PDF 

Dalerba P, Sahoo D, Paik S, Guo X, Yothers G, Song N, Wilcox-Fogel N, Forgó E, Rajendran PS, Miranda SP, Hisamori S, Hutchison J, Kalisky T, Qian D, Wolmark N, Fisher GA, van de Rijn M, Clarke MF. CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer.   N Engl J Med. 2016 Jan 21;374(3):211-22. doi: 10.1056/NEJMoa1506597.  PubMed.   PDF

2015

Bishara A, Liu Y, Weng Z, Kashef-Haghighi D, Newburger DE, West R, Sidow A, Batzoglou S. Read clouds uncover variation in complex regions of the human genome. Genome Res. 2015 Oct;25(10):1570-80. doi: 10.1101/gr.191189.115. Epub 2015 Aug 18. PubMed PDF 

Gentles AJ, Bratman SV, Lee LJ, Harris JP, Feng W, Nair RV, Shultz DB, Nair VS, Hoang CD, West RB, Plevritis SK, Alizadeh AA, Diehn M.Integrating Tumor and Stromal Gene Expression Signatures With Clinical Indices for Survival Stratification of Early-Stage Non-Small Cell Lung Cancer.  J Natl Cancer Inst. 2015 Aug 18;107(10). pii: djv211. doi: 10.1093/jnci/djv211. PubMed   PDF 

Afghahi A, Forgó E, Mitani AA, Desai M, Varma S, Seto T, Rigdon J, Jensen KC, Troxell ML, Gomez SL, Das AK, Beck AH, Kurian AW, West RB.  Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer. Breast Cancer Res. 2015 Aug 13;17:108. doi: 10.1186/s13058-015-0623-y.  PubMed   PDF 

Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, Nair VS, Xu Y, Khuong A, Hoang CD, Diehn M, West RB, Plevritis SK, Alizadeh AA. The prognostic landscape of genes and infiltrating immune cells across human cancers.  Nat Med. 2015 Aug;21(8):938-45. doi: 10.1038/nm.3909. PubMed   PDF 

Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, Chmielowski B, Staddon AP, Cohn AL, Shapiro GI, Keedy VL, Singh AS, Puzanov I, Kwak EL, Wagner AJ, Von Hoff DD, Weiss GJ, Ramanathan RK, Zhang J, Habets G, Zhang Y, Burton EA, Visor G, Sanftner L, Severson P, Nguyen H, Kim MJ, Marimuthu A, Tsang G, Shellooe R, Gee C, West BL, Hirth P, Nolop K, van de Rijn M, Hsu HH, Peterfy C, Lin PS, Tong-Starksen S, Bollag G. Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor.   N Engl J Med. 2015 Jul 30;373(5):428-37. doi: 10.1056/NEJMoa1411366. PubMed .  PDF

Riordan DP, Varma S, West RB, Brown PO. Automated Analysis and Classification of Histological Tissue Features by Multi-Dimensional Microscopic Molecular Profiling. 
PLoS One. 2015 Jul 15;10(7):e0128975. doi: 10.1371/journal.pone.0128975.  PubMed . PDF  

Chen EC, Karl TA, Kalisky T, Gupta SK, O'Brien CA, Longacre TA, van de Rijn M, Quake SR, Clarke MF, Rothenberg ME.  KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and is Upregulated in a Subset of Human Colon Cancers.  Gastroenterology. 2015 May 27. pii: S0016-5085(15)00769-6. doi: 10.1053/j.gastro.2015.05.042. [Epub ahead of print]  PubMed   PDF

Popic V, Salari R, Hajirasouliha I, Kashef-Haghighi D, West RB, Batzoglou S. Fast and scalable inference of multi-sample cancer lineagesGenome Biol. 2015 May 6;16:91. doi: 10.1186/s13059-015-0647-8. PubMed   PDF 

McClary AC1, West RB, McClary AC, Pollack JR, Fischbein NJ, Holsinger CF, Sunwoo J, Colevas AD, Sirjani D. Ameloblastoma: a clinical review and trends in management.  Eur Arch Otorhinolaryngol. 2015 Apr 30. [Epub ahead of print]  PubMed  PDF

Weng Z, Spies N, Zhu SX, Newburger DE, Kashef-Haghighi D, Batzoglou S, Sidow A, West RB. Cell-lineage heterogeneity and driver mutation recurrence in pre-invasive breast neoplasia. Genome Med. 2015 Apr 9;7(1):28. doi: 10.1186/s13073-015-0146-2. eCollection 2015.  PubMed PDF

Guo X, Jo VY, Mills A, Zhu S, Lee CH, Espinosa I, Nucci MR, Varma S, Forgo E, Hastie T, Anderson S, Ganjoo K, Beck AH, West R, Fletcher C, van de Rijn M.  Clinically relevant molecular subtypes in leiomyosarcoma.  Clin Cancer Res. 2015 Apr 20. pii: clincanres.3141.2014. [Epub ahead of print]  PubMed   PDF

Ang D, Ballard M, Beadling C, Warrick A, Schilling A, O'Gara R, Pukay M, Neff TL, West RB, Corless CL, Troxell ML. Novel mutations in neuroendocrine carcinoma of the breast: possible therapeutic targets.   Appl Immunohistochem Mol Morphol. 2015 Feb;23(2):97-103. doi: 10.1097/PDM.0b013e3182a40fd1. PubMed   PDF

Riess JW, West R, Dean M, Klimowicz AC, Neal JW, Hoang C, Wakelee HA  GLI1, CTNNB1 and NOTCH1 protein expression in a thymic epithelial malignancy tissue microarray. Anticancer Res. 2015 Feb;35(2):669-76.  PubMed   PDF

Liang Y, Padda SK, Riess JW, West RB, Neal JW, Wakelee HA.  Pemetrexed in patients with thymic malignancies previously treated with chemotherapy. Lung Cancer. 2015 Jan;87(1):34-8. doi: 10.1016/j.lungcan.2014.11.006. Epub 2014 Nov 15.  PubMed   PDF

2014

Marques Howarth M, Simpson D, Ngok SP, Nieves B, Chen R, Siprashvili Z, Vaka D, Breese MR, Crompton BD, Alexe G, Hawkins DS, Jacobson D, Brunner AL, West R, Mora J, Stegmaier K, Khavari P, Sweet-Cordero EA. Long noncoding RNA EWSAT1-mediated gene repression facilitates Ewing sarcoma oncogenesis.  J Clin Invest. 2014 Nov 17. pii: 72124. doi: 10.1172/JCI72124  PubMed   PDF

Padda SK, Riess JW, Schwartz EJ, Tian L, Kohrt HE, Neal JW, West RB, Wakelee HA. Diffuse High Intensity PD-L1 Staining in Thymic Epithelial Tumors.  J Thorac Oncol. 2014 Nov 14.  PubMed   PDF

Scheeren FA, Kuo AH, van Weele LJ, Cai S, Glykofridis I, Sikandar SS, Zabala M, Qian D, Lam JS, Johnston D, Volkmer JP, Sahoo D, van de Rijn M, Dirbas FM, Somlo G6, Kalisky T, Rothenberg ME, Quake SR, Clarke MF.  A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis.  Nat Cell Biol. 2014 Nov 2. doi: 10.1038/ncb3058  PubMed   PDF

Pan Y, Volkmer JP, Mach KE, Rouse RV, Liu JJ, Sahoo D, Chang TC, Metzner TJ, Kang L, van de Rijn M, Skinner EC, Gambhir SS, Weissman IL, Liao JC.  Endoscopic molecular imaging of human bladder cancer using a CD47 antibody. Sci Transl Med. 2014 Oct 29;6(260):260ra148. doi: 10.1126/scitranslmed.3009457. Epub 2014 Oct 29.  PubMed   PDF

Keire PA, Bressler SL, Lemire JM, Edris B, Rubin BP, Rahmani M, McManus BM, van de Rijn M, Wight TN. A role for versican in the development of leiomyosarcoma. J Biol Chem. 2014 Oct 15. pii: jbc.M114.607168  PubMed   PDF

Carvalho FM, Bacchi LM, Pincerato KM, Van de Rijn M, Bacchi CE. Geographic differences in the distribution of molecular subtypes of breast cancer in Brazil. BMC Womens Health. 2014 Aug 29;14:102. doi: 10.1186/1472-6874-14-102. PubMed  PDF

Demicco EG, Boland GM, Brewer Savannah KJ, Lusby K, Young ED, Ingram D, Watson KL, Bailey M, Guo X, Hornick JL, van de Rijn M, Wang WL, Torres KE, Lev D, Lazar AJ. Progressive Loss Of Myogenic Differentiation In Leiomyosarcoma Has Prognostic Value. Histopathology. 2014 May 30. doi: 10.1111/his.12466. [Epub ahead of print]  PubMed  PDF

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Sweeney RT, McClary AC, Myers BR, Biscocho J, Neahring L, Kwei KA, Qu K, Gong X, Ng T, Jones CD, Varma S, Odegaard JI, Sugiyama T, Koyota S, Rubin BP, Troxell ML, Pelham RJ, Zehnder JL, Beachy PA, Pollack JR, West RB. Identification of recurrent SMO and BRAF mutations in ameloblastomas.  Nat Genet. 2014 May 25. doi: 10.1038/ng.2986. PubMed   PDF

Wang Y, Marino-Enriquez A, Bennett RR, Zhu M, Shen Y, Eilers G, Lee JC, Henze J, Fletcher BS, Gu Z, Fox EA, Antonescu CR, Fletcher CD, Guo X, Raut CP, Demetri GD, van de Rijn M, Ordog T, Kunkel LM, Fletcher JA. Dystrophin is a tumor suppressor in human cancers with myogenic programs.  Nat Genet. 2014 Jun;46(6):601-6. doi: 10.1038/ng.2974. Epub 2014 May 4. PubMed  PDF

Nair VS, Gevaert O, Davidzon G, Plevritis SK, West R.  NF-κB protein expression associates with 18F-FDG PET tumor uptake in non-small cell lung cancer: A radiogenomics validation study to understand tumor metabolism.  Lung Cancer.   2014 Feb;83(2):189-96. doi: 10.1016/j.lungcan.2013.11.001. Epub 2013 Nov 13..  PubMed   PDF

Last update June 20, 2016