Erna Forgo

All Publications

• INSM1 Expression in Clear Cell Sarcoma of Kidney and other BCOR-Rearranged Tumors Wang, H., Forgo, E., Clay, M., Al-Ibraheemi, A., Charville, G. NATURE PUBLISHING GROUP. 2020: 835–36

  View details for Web of Science ID 000518328801397

• 5-hmC Immunohistochemistry is a Reliable Marker for Predicting Leiomyomas with Fumarate Hydratase Mutations Sharma, A., Forgo, E., Howitt, B., Rabban, J., Garg, K., Bennett, J. NATURE PUBLISHING GROUP. 2020: 1134–35

  View details for Web of Science ID 000518328902329

• DNA Methylation Profiling of Uterine Sarcomas Forgo, E., Lang, A., Natu, V., Longacre, T., Bennett, J., Quick, C., Parra-Herran, C., Nucci, M., Kolin, D., Howitt, B. NATURE PUBLISHING GROUP. 2020: 1056–57

  View details for Web of Science ID 000518328902244

• A human lung tumor microenvironment interactome identifies clinically relevant cell-type cross-talk. Genome biology Gentles, A. J., Hui, A. B., Feng, W., Azizi, A., Nair, R. V., Bouchard, G., Knowles, D. A., Yu, A., Jeong, Y., Bejnood, A., Forgó, E., Varma, S., Xu, Y., Kuong, A., Nair, V. S., West, R., van de Rijn, M., Hoang, C. D., Diehn, M., Plevritis, S. K. 2020; 21 (1): 107

  Abstract

  Tumors comprise a complex microenvironment of interacting malignant and stromal cell types. Much of our understanding of the tumor microenvironment comes from in vitro studies isolating the interactions between malignant cells and a single stromal cell type, often along a single pathway.To develop a deeper understanding of the interactions between cells within human lung tumors, we perform RNA-seq profiling of flow-sorted malignant cells, endothelial cells, immune cells, fibroblasts, and bulk cells from freshly resected human primary non-small-cell lung tumors. We map the cell-specific differential expression of prognostically associated secreted factors and cell surface genes, and computationally reconstruct cross-talk between these cell types to generate a novel resource called the Lung Tumor Microenvironment Interactome (LTMI). Using this resource, we identify and validate a prognostically unfavorable influence of Gremlin-1 production by fibroblasts on proliferation of malignant lung adenocarcinoma cells. We also find a prognostically favorable association between infiltration of mast cells and less aggressive tumor cell behavior.These results illustrate the utility of the LTMI as a resource for generating hypotheses concerning tumor-microenvironment interactions that may have prognostic and therapeutic relevance.

  View details for DOI 10.1186/s13059-020-02019-x

  View details for PubMedID 32381040

• Detection of Circulating Tumor DNA in Patients With Uterine Leiomyomas JCO PRECISION ONCOLOGY Przybyl, J., Spans, L., Lum, D. A., Zhu, S., Vennam, S., Forgo, E., Varma, S., Ganjoo, K., Hastie, T., Bowen, R., Debiec-Rychter, M., van de Rijn, M. 2019; 3

  View details for DOI 10.1200/PO.18.00409

  View details for Web of Science ID 000491150900001

• Morphologic, Immunophenotypic and Molecular Features of Hypermutation in Colorectal Carcinomas with Mutations in DNA Polymerase Ɛ (POLE). Histopathology Forgó, E., Gomez, A. J., Steiner, D., Zehnder, J., Longacre, T. A. 2019

  Abstract

  Colorectal carcinomas (CRC) with mismatch repair (MMR) deficiency have increased tumor mutation burden and respond to immune checkpoint inhibitor therapy. The Cancer Genome Atlas identified hypermutated CRCs with somatic mutations in DNA polymerase ε (POLE) with mutation burdens exceeding that of MMR-deficient CRCs.To identify the morphologic, immunophenotypic and molecular features of POLE mutated CRCs, 63 consecutive MMR-intact CRCs were evaluated by Sanger sequencing for POLE exonuclease domain mutations in exons 9, 11, 13 and 14 and confirmed by next generation sequencing. Tumor immune microenvironment and immunoscores were assessed in POLE-mutated CRCs using immunohistochemistry to detect CD3+/CD8+ tumor-infiltrating lymphocytes and compared to 59 non-POLE mutated MMR-intact CRC, 10 non-POLE mutated MMR-deficient CRCs, and 223 normal colonic mucosa.4.8% CRC (4 MMR-intact primary and 1 MMR-intact metastasis) harbored POLE mutations in amino acid 286 in exon 9 (p.P286R) or exon 13 (p.V411L). POLE mutated CRCs arose in the transverse colon and rectum, were male-predominant, younger, and showed increased tumor-infiltrating lymphocytes and immune cells at the tumor-stromal interface. The patient with metastatic POLE mutated CRC was placed on PD-1 inhibitor treatment with marked and sustained response. These data indicate that POLE mutated CRCs have hypermutated phenotypes despite MMR-intact status, with mutation burdens higher than that in microsatellite unstable CRCs. Given the recent approval for treatment of microsatellite unstable cancer with immune checkpoint inhibitors, assessment of POLE status may help guide therapeutic decisions for hypermutated tumors with intact MMR that would otherwise be missed by routine testing.

  View details for DOI 10.1111/his.13984

  View details for PubMedID 31479159

• Plurihormonal pituitary neuroendocrine tumor with Pit1 and SF-1 coexpression: A novel entity Jonathan, L., Forgo, E., Katznelson, L., Harsh, G., Vogel, H. OXFORD UNIV PRESS INC. 2018: 523

  View details for Web of Science ID 000434064400181

• Combination Approach for Detecting Different Types of Alterations in Circulating Tumor DNA in Leiomyosarcoma CLINICAL CANCER RESEARCH Przybyl, J., Chabon, J. J., Spans, L., Ganjoo, K. N., Vennam, S., Newman, A. M., Forgo, E., Varma, S., Zhu, S., Debiec-Rychter, M., Alizadeh, A. A., Diehn, M., van de Rijn, M. 2018; 24 (11): 2688–99

  View details for DOI 10.1158/1078-0432.CCR-17-3704

  View details for Web of Science ID 000433971400023

• Practical Approach to the Use of Helicobacter Immunohistochemistry Based on a Single-Institution Retrospective Quality Assurance Review Forgo, E., Longacre, T., Martin, B. NATURE PUBLISHING GROUP. 2018: 774–75

  View details for Web of Science ID 000429308605030

• Clinicopathologic Features of Mismatch Repair Protein-Deficient Non-Colorectal Gastrointestinal, Esophageal and Pancreatic Adenocarcinomas Forgo, E., Charville, G., Longacre, T. NATURE PUBLISHING GROUP. 2018: 261

  View details for Web of Science ID 000459341001198

• PAX7 Expression in Rhabdomyosarcoma, Related Soft Tissue Tumors, and Small Round Blue Cell Neoplasms. American journal of surgical pathology Charville, G. W., Varma, S., Forgó, E., Dumont, S. N., Zambrano, E., Trent, J. C., Lazar, A. J., van de Rijn, M. 2016; 40 (10): 1305-1315

  Abstract

  Rhabdomyosarcoma, the most common soft tissue malignancy of childhood, is a morphologically variable tumor defined by its phenotype of skeletal muscle differentiation. The diagnosis of rhabdomyosarcoma often relies in part on the identification of myogenic gene expression using immunohistochemical or molecular techniques. However, these techniques show imperfect sensitivity and specificity, particularly in scant tissue biopsies. Here, we expand the toolkit for rhabdomyosarcoma diagnosis by studying the expression of PAX7, a transcriptional regulator of mammalian muscle progenitor cells implicated in the pathogenesis of rhabdomyosarcoma. Immunohistochemical analysis of tissue microarrays using a monoclonal anti-PAX7 antibody was used to characterize PAX7 expression in 25 non-neoplastic tissues, 109 rhabdomyosarcomas, and 697 small round blue cell or other soft tissue tumors. Among non-neoplastic tissues, PAX7 was specifically expressed in adult muscle progenitor cells (satellite cells). In embryonal rhabdomyosarcoma, PAX7 expression was positive in 52 of 63 cases (83%), negative in 9 of 63 cases (14%), and focal in 2 of 63 cases (3%). PAX7-positive embryonal rhabdomyosarcoma cases included several showing focal or negative myogenin expression. PAX7 expression in alveolar rhabdomyosarcoma was positive in 6 of 31 cases (19%), negative in 14 of 31 cases (45%), and focal in 11 of 31 cases (36%). In addition, PAX7 was expressed in 5 of 7 pleomorphic rhabdomyosarcomas (71%) and 6 of 8 spindle cell rhabdomyosarcomas (75%). Among histologic mimics, only Ewing sarcoma showed PAX7 expression (7/7 cases, 100%). In contrast, expression of PAX7 was not seen in the large majority (688/690, 99.7%) of examined cases of other soft tissue tumors, small round blue cell neoplasms, and leukemias/lymphomas. In summary, immunohistochemical analysis of PAX7 expression may be a useful diagnostic tool in the assessment of skeletal muscle differentiation in human tumors.

  View details for DOI 10.1097/PAS.0000000000000717

  View details for PubMedID 27526298

• Transcriptome sequencing analysis of four psammomatous meningiomas Samghabadi, P., Forgo, E., West, R., Vogel, H. LIPPINCOTT WILLIAMS & WILKINS. 2016: 575

  View details for Web of Science ID 000377665000038

• 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

  View details for Web of Science ID 000369270700157

• CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer NEW ENGLAND JOURNAL OF MEDICINE Dalerba, P., Sahoo, D., Paik, S., Guo, X., Yothers, G., Song, N., Wilcox-Fogel, N., Forgo, E., Rajendran, P. S., Miranda, S. P., Hisamori, S., Hutchison, J., Kalisky, T., Qian, D., Wolmark, N., Fisher, G. A., van de Rijn, M., Clarke, M. F. 2016; 374 (3): 211-222

  Abstract

  Background The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. Methods We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy. Results The transcription factor CDX2 ranked first in our screening test. A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression. In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P=0.002). In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein-negative colon cancers than among the 276 (87.9%) with CDX2 protein-positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003). In both these groups, these findings were independent of the patient's age, sex, and tumor stage and grade. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P=0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P=0.004). In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P=0.006). Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.).

  View details for DOI 10.1056/NEJMoa1506597

  View details for Web of Science ID 000368404800006

  View details for PubMedCentralID PMC4784450

• Molecular subtyping of leiomyosarcoma with 3' end RNA sequencing. Genomics data Guo, X., Forgó, E., van de Rijn, M. 2015; 5: 366-367

  Abstract

  Leiomyosarcoma (LMS) is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for LMS. We performed expression profiling on 99 cases of LMS with 3'end RNA sequencing (3SEQ) and demonstrated the existence of 3 molecular subtypes in this cohort. We consequently showed that these molecular subtypes are reproducible using an independent cohort of 82 LMS cases from TCGA. Two new formalin-fixed, paraffin-embedded (FFPE) tissue-compatible diagnostic immunohistochemical markers were identified for two of the three subtypes: LMOD1 for subtype I LMS and ARL4C for subtype II LMS. Subtype I and subtype II LMS were associated with good and poor prognosis, respectively. Here, we describe the details of LMS diagnosis, RNA isolation, 3SEQ library construction, 3SEQ sequencing data analysis and molecular subtype determination. The 3SEQ data produced in this study was deposited into Gene Expression Omnibus (GEO) under GSE45510.

  View details for PubMedID 26240788

• 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

• 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

• 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

  View details for Web of Science ID 000348948000169

• Chromosomal copy number alterations (CNAs) for risk assessment of ductal carcinoma in situ (DCIS) Afghahi, A., Forgo, E., Mitani, A., Desai, M., Varma, S., Seto, T., Jensen, K. C., Gomez, S., Das, A. K., Beck, A. H., Kurian, A. W., West, R. B. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613202339