Lisa Zaba, MD, PhD

All Publications

• Increased Mortality in Asians With Systemic Sclerosis in Northern California. ACR open rheumatology Chung, M. P., Dontsi, M., Postlethwaite, D., Kesh, S., Simard, J. F., Fiorentino, D., Zaba, L. C., Chung, L. 2020

  Abstract

  OBJECTIVE: The objective of this study is to evaluate racial/ethnic differences in disease manifestations and survival in a US cohort of patients with systemic sclerosis (SSc), with a focus on Asian patients.METHODS: A retrospective cohort study was conducted among Kaiser Permanente Northern California adults with an incident SSc diagnosis by a rheumatologist from 2007 to 2016, confirmed by a chart review to fulfill 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria. Self-reported race/ethnicity was categorized as non-Hispanic white, Asian, Hispanic, and black. Disease manifestations and survival were compared, using white patients as the reference.RESULTS: A total of 609 patients with incident SSc were identified: 89% were women, and 81% had limited cutaneous SSc, with a mean age at diagnosis of 55.4 ± 14.8 years. The racial/ethnic distribution was 51% non-Hispanic white (n = 310), 25% Hispanic (n = 154), 16% Asian (n = 96), and 8% black (n = 49). Compared with white patients, black patients had a greater prevalence of diffuse disease (14.5% vs. 44.9%; P < 0.001), and Asians had higher rates of anti-U1-RNP antibodies (32.1% vs. 11.9%; P = 0.005). Nine-year overall survival rates following SSc diagnosis were lower in Asian (52.3%), black (52.2%), and Hispanic patients (68.2%) compared with white patients (75.8%). Pulmonary hypertension and infections were the leading causes of death in Asian patients. Asian race was associated with higher mortality on univariable (hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.08-2.99]; P = 0.020) and multivariable analyses (HR 1.80 [95% CI 0.99-3.16]; P = 0.047) when adjusting for age, sex, body mass index, cutaneous subtype, smoking status, interstitial lung disease, pulmonary hypertension, renal crisis, and malabsorption syndrome.CONCLUSION: Asian patients with SSc in this US cohort had increased mortality compared with white patients. These patients warrant close monitoring for disease progression.

  View details for DOI 10.1002/acr2.11126

  View details for PubMedID 32198914

• Cutaneous Pleomorphic Fibromas Arising in Patients with Germline TP53 Mutations. Journal of cutaneous pathology Cloutier, J. M., Shalin, S. C., Lindberg, M., Gardner, J. M., Fernandez-Pol, S., Zaba, L., Novoa, R., Brown, R. A. 2020

  Abstract

  Pleomorphic fibromas are rare benign cutaneous neoplasms associated with deletion/loss of chromosomes 13q and 17p, where RB1 and TP53 are located, respectively. Herein, we report five cases of pleomorphic fibroma arising in patients with germline TP53 mutations, suggesting a potential link with Li-Fraumeni syndrome. All three patients were female and young (mean age 27) with a strong personal and/or family oncologic history and confirmed pathogenic germline TP53 mutations. In two patients, multiple pleomorphic fibromas were diagnosed. Clinically, the lesions arose at various cutaneous sites and were small (?2cm) and raised (4/5). Histologically, the tumors were paucicellular, comprised of atypical spindled to stellate cells with hyperchromatic and variably pleomorphic nuclei. Mitotic activity was exceedingly low, although rare atypical mitotic figures were seen in one case. Immunohistochemically, the tumor cells were diffusely positive for p16 (3/3) and showed loss of Rb expression (5/5). All cases showed aberrant p53 expression (overexpression in 4, complete loss in 1). The tumors have followed a benign clinical course with no evidence of progression or recurrence. In conclusion, the development of multiple pleomorphic fibromas in a young patient may be a clue to an underlying genetic cancer syndrome involving TP53. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/cup.13686

  View details for PubMedID 32187703

• Prognostic value of volumetric PET parameters at early response evaluation in melanoma patients treated with immunotherapy. European journal of nuclear medicine and molecular imaging Nakamoto, R., Zaba, L. C., Rosenberg, J., Reddy, S. A., Nobashi, T. W., Davidzon, G., Aparici, C. M., Nguyen, J., Moradi, F., Iagaru, A., Franc, B. L. 2020

  Abstract

  The purpose of this study was to investigate the prognostic value of whole-body metabolic tumor volume (MTV) and other metabolic tumor parameters, obtained from baseline and first restaging 18F-FDG PET/CT scans in melanoma patients treated with immune checkpoint inhibitors (ICIs).Eighty-five consecutive melanoma patients (M, 57; F, 28) treated with ICIs who underwent PET/CT scans before and approximately 3 months after the start of immunotherapy were retrospectively enrolled. Metabolic tumor parameters including MTV for all melanoma lesions were measured on each scan. A Cox proportional hazards model was used for univariate and multivariate analyses of metabolic parameters combined with known clinical prognostic factors associated with overall survival (OS). Kaplan-Meier curves for patients dichotomized based on median values of imaging parameters were generated.The median OS time in all patients was 45 months (95% CI 24-45 months). Univariate analysis demonstrated that MTV obtained from first restaging PET/CT scans (MTVpost) was the strongest prognostic factor for OS among PET/CT parameters (P 

  View details for DOI 10.1007/s00259-020-04792-0

  View details for PubMedID 32296882

• Increased Mortality in Black and Asian Patients with Systemic Sclerosis in Northern California Chung, M., Dontsi, M., Postlethwaite, D., Kesh, S., Zaba, L., Chung, L. WILEY. 2018

  View details for Web of Science ID 000447268905018

• Chromatin Accessibility Landscape of Cutaneous T Cell Lymphoma and Dynamic Response to HDAC Inhibitors. Cancer cell Qu, K., Zaba, L. C., Satpathy, A. T., Giresi, P. G., Li, R., Jin, Y., Armstrong, R., Jin, C., Schmitt, N., Rahbar, Z., Ueno, H., Greenleaf, W. J., Kim, Y. H., Chang, H. Y. 2017

  Abstract

  Here, we define the landscape and dynamics of active regulatory DNA in cutaneous T cell lymphoma (CTCL) by ATAC-seq. Analysis of 111 human CTCL and control samples revealed extensive chromatin signatures that distinguished leukemic, host, and normal CD4(+) T cells. We identify three dominant patterns of transcription factor (TF) activation that drive leukemia regulomes, as well as TF deactivations that alter host T cells in CTCL patients. Clinical response to histone deacetylase inhibitors (HDACi) is strongly associated with a concurrent gain in chromatin accessibility. HDACi causes distinct chromatin responses in leukemic and host CD4(+) T cells, reprogramming host T cells toward normalcy. These results provide a foundational framework to study personal regulomes in human cancer and epigenetic therapy.

  View details for PubMedID 28625481

• Individuality and variation of personal regulomes in primary human T cells. Cell systems Qu, K., Zaba, L. C., Giresi, P. G., Li, R., Longmire, M., Kim, Y. H., Greenleaf, W. J., Chang, H. Y. 2015; 1 (1): 51-61

  Abstract

  Here we survey variation and dynamics of active regulatory elements genome-wide using longitudinal samples from human individuals. We applied Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) to map chromatin accessibility in primary CD4+ T cells isolated from standard blood draws of 12 healthy volunteers over time, from cancer patients, and during T cell activation. Over 4,000 predicted regulatory elements (7.2%) showed reproducible variation in accessibility between individuals. Gender was the most significant attributable source of variation. ATAC-seq revealed previously undescribed elements that escape X chromosome inactivation and predicted gender-specific gene regulatory networks across autosomes, which coordinately affect genes with immune function. Noisy regulatory elements with personal variation in accessibility are significantly enriched for autoimmune disease loci. Over one third of regulome variation lacked genetic variation in cis, suggesting contributions from environmental or epigenetic factors. These results refine concepts of human individuality and provide a foundational reference for comparing disease-associated regulomes.

  View details for PubMedID 26251845

• Individuality and Variation of Personal Regulomes in Primary Human T Cells CELL SYSTEMS Qu, K., Zaba, L. C., Giresi, P. G., Li, R., Longmire, M., Kim, Y. H., Greenleaf, W. J., Chang, H. Y. 2015; 1 (1): 51-61

  Abstract

  Here we survey variation and dynamics of active regulatory elements genome-wide using longitudinal samples from human individuals. We applied Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) to map chromatin accessibility in primary CD4+ T cells isolated from standard blood draws of 12 healthy volunteers over time, from cancer patients, and during T cell activation. Over 4,000 predicted regulatory elements (7.2%) showed reproducible variation in accessibility between individuals. Gender was the most significant attributable source of variation. ATAC-seq revealed previously undescribed elements that escape X chromosome inactivation and predicted gender-specific gene regulatory networks across autosomes, which coordinately affect genes with immune function. Noisy regulatory elements with personal variation in accessibility are significantly enriched for autoimmune disease loci. Over one third of regulome variation lacked genetic variation in cis, suggesting contributions from environmental or epigenetic factors. These results refine concepts of human individuality and provide a foundational reference for comparing disease-associated regulomes.

  View details for DOI 10.1016/j.cels.2015.06.003

  View details for Web of Science ID 000209925400012

  View details for PubMedCentralID PMC4522940

• Distinctive cutaneous and systemic features associated with antitranscriptional intermediary factor-1? antibodies in adults with dermatomyositis. Journal of the American Academy of Dermatology Fiorentino, D. F., Kuo, K., Chung, L., Zaba, L., Li, S., Casciola-Rosen, L. 2015; 72 (3): 449-455

  Abstract

  Antibodies against transcriptional intermediary factor (TIF)-1? are associated with malignancy in dermatomyositis (DM). Identification of clinical findings associated with anti-TIF-1? antibodies in DM is a high priority for both patient diagnosis and risk assessment.We sought to define the clinical phenotype of patients with anti-TIF-1? DM.Using a novel, sensitive, and specific assay for anti-TIF-1? antibodies, we retrospectively tested plasma from 134 adult patients with DM and examined associations between anti-TIF-1? antibodies and particular clinical and laboratory features.In all, 55 (41%) patients had autoantibodies to TIF-1?. Anti-TIF-1? positive patients were less likely to have systemic features including interstitial lung disease, Raynaud phenomenon, and arthritis/arthralgia. Patients with TIF-1? autoantibodies had more extensive skin involvement, and some patients manifested characteristic findings including palmar hyperkeratotic papules, psoriasis-like lesions and a novel finding of hypopigmented and telangiectatic ("red on white") patches.This was a retrospective study from a single tertiary referral center.TIF-1? is the most commonly targeted DM-specific autoantigen in adults in a large US cohort. Although these patients tend to have less systemic involvement, their skin disease is often extensive and characteristic. Recognition of cutaneous findings in anti-TIF-1? positive patients may allow more accurate and timely diagnosis and effective treatment of patients with DM.

  View details for DOI 10.1016/j.jaad.2014.12.009

  View details for PubMedID 25595720

• Transposition of Native Chromatin for Fast and Sensitive Mulitmodal Analysis of Chromatin Architecture Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y., Greenleaf, W. J. CELL PRESS. 2014: 77A

  View details for DOI 10.1016/j.bpj.2013.11.503

  View details for Web of Science ID 000337000400397

• Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nature methods Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y., Greenleaf, W. J. 2013; 10 (12): 1213-1218

  Abstract

  We describe an assay for transposase-accessible chromatin using sequencing (ATAC-seq), based on direct in vitro transposition of sequencing adaptors into native chromatin, as a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq captures open chromatin sites using a simple two-step protocol with 500-50,000 cells and reveals the interplay between genomic locations of open chromatin, DNA-binding proteins, individual nucleosomes and chromatin compaction at nucleotide resolution. We discovered classes of DNA-binding factors that strictly avoided, could tolerate or tended to overlap with nucleosomes. Using ATAC-seq maps of human CD4(+) T cells from a proband obtained on consecutive days, we demonstrated the feasibility of analyzing an individual's epigenome on a timescale compatible with clinical decision-making.

  View details for DOI 10.1038/nmeth.2688

  View details for PubMedID 24097267

• Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position NATURE METHODS Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y., Greenleaf, W. J. 2013; 10 (12): 1213-?

  Abstract

  We describe an assay for transposase-accessible chromatin using sequencing (ATAC-seq), based on direct in vitro transposition of sequencing adaptors into native chromatin, as a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq captures open chromatin sites using a simple two-step protocol with 500-50,000 cells and reveals the interplay between genomic locations of open chromatin, DNA-binding proteins, individual nucleosomes and chromatin compaction at nucleotide resolution. We discovered classes of DNA-binding factors that strictly avoided, could tolerate or tended to overlap with nucleosomes. Using ATAC-seq maps of human CD4(+) T cells from a proband obtained on consecutive days, we demonstrated the feasibility of analyzing an individual's epigenome on a timescale compatible with clinical decision-making.

  View details for DOI 10.1038/NMETH.2688

  View details for Web of Science ID 000327698100025

  View details for PubMedID 24097267

• Most Patients With Cancer-Associated Dermatomyositis Have Antibodies to Nuclear Matrix Protein NXP-2 or Transcription Intermediary Factor 1?. Arthritis and rheumatism Fiorentino, D. F., Chung, L. S., Christopher-Stine, L., Zaba, L., Li, S., Mammen, A. L., Rosen, A., Casciola-Rosen, L. 2013; 65 (11): 2954-2962

  Abstract

  Since dermatomyositis (DM) is associated with an increased risk of malignancy, accurate identification of patients likely to harbor cancers is important. Using immunoprecipitations from radiolabeled cell lysates, several groups recently showed that anti-transcription intermediary factor 1? (anti-TIF-1?) antibodies are associated with malignancy in DM. We undertook this study to develop sensitive, specific assays to detect antibodies against TIF-1? and nuclear matrix protein NXP-2 and to evaluate their association with malignancy in DM.To detect anti-TIF-1? antibodies, immunoprecipitations were performed using lysates made from HeLa cells overexpressing TIF-1?, with detection by immunoblotting. Anti-NXP-2 antibodies were assayed by immunoprecipitation using (35) S-methionine-labeled NXP-2 generated by in vitro transcription/translation. We analyzed patient sera from DM cohorts seen at the Stanford University Dermatology Clinic (n = 111) and the Johns Hopkins Myositis Center (n = 102).A total of 17% and 38% of patients had antibodies against NXP-2 and TIF-1?, respectively. Reactivity against either NXP-2 or TIF-1? identified 83% of patients with cancer-associated DM. In addition to older age and male sex, cancer was associated with antibodies to NXP-2 or TIF-1? on multivariate analysis (odds ratio 3.78 [95% confidence interval 1.33-10.8]). Stratification by sex revealed that anti-NXP-2 was specifically associated with cancer in males (odds ratio 5.78 [95% confidence interval 1.35-24.7]).These studies demonstrate that anti-NXP-2 and anti-TIF-1? antibodies are frequent DM specificities (found in 55% of patients) and are present in most patients with cancer-associated DM.

  View details for DOI 10.1002/art.38093

  View details for PubMedID 24037894

• Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1?. Arthritis and rheumatism Fiorentino, D. F., Chung, L. S., Christopher-Stine, L., Zaba, L., Li, S., Mammen, A. L., Rosen, A., Casciola-Rosen, L. 2013; 65 (11): 2954-2962

  Abstract

  Since dermatomyositis (DM) is associated with an increased risk of malignancy, accurate identification of patients likely to harbor cancers is important. Using immunoprecipitations from radiolabeled cell lysates, several groups recently showed that anti-transcription intermediary factor 1? (anti-TIF-1?) antibodies are associated with malignancy in DM. We undertook this study to develop sensitive, specific assays to detect antibodies against TIF-1? and nuclear matrix protein NXP-2 and to evaluate their association with malignancy in DM.To detect anti-TIF-1? antibodies, immunoprecipitations were performed using lysates made from HeLa cells overexpressing TIF-1?, with detection by immunoblotting. Anti-NXP-2 antibodies were assayed by immunoprecipitation using (35) S-methionine-labeled NXP-2 generated by in vitro transcription/translation. We analyzed patient sera from DM cohorts seen at the Stanford University Dermatology Clinic (n = 111) and the Johns Hopkins Myositis Center (n = 102).A total of 17% and 38% of patients had antibodies against NXP-2 and TIF-1?, respectively. Reactivity against either NXP-2 or TIF-1? identified 83% of patients with cancer-associated DM. In addition to older age and male sex, cancer was associated with antibodies to NXP-2 or TIF-1? on multivariate analysis (odds ratio 3.78 [95% confidence interval 1.33-10.8]). Stratification by sex revealed that anti-NXP-2 was specifically associated with cancer in males (odds ratio 5.78 [95% confidence interval 1.35-24.7]).These studies demonstrate that anti-NXP-2 and anti-TIF-1? antibodies are frequent DM specificities (found in 55% of patients) and are present in most patients with cancer-associated DM.

  View details for DOI 10.1002/art.38093

  View details for PubMedID 24037894

• Skin disease in dermatomyositis CURRENT OPINION IN RHEUMATOLOGY Zaba, L. C., Fiorentino, D. F. 2012; 24 (6): 597-601

  Abstract

  This review will provide the clinician with an update on the pathogenesis, clinical manifestations, and therapy for skin disease in dermatomyositis. Recent insights into the role for interferon in skin disease as well as the development and validation of quantitative tools to measure skin disease activity allow the possibility that, for the first time, dermatomyositis skin disease can serve as a valid outcome for clinical trials of targeted therapies. Also, the increasing appreciation of the heterogeneity of skin disease in dermatomyositis has already provided evidence that clinical subtypes of disease can provide important prognostic and diagnostic information to the clinician.It is becoming apparent that the skin inflammation alone has implications for systemic and malignancy risk in dermatomyositis patients, and that there may be several pathogenic similarities between muscle and skin inflammation in dermatomyositis. Recent data on therapy for calcinosis cutis highlights that more prospective studies are needed to evaluate how best to manage all manifestations of skin inflammation in dermatomyositis.A more careful description and classification of skin disease in dermatomyositis may allow the clinician to predict more accurately which patients will be at higher risk for cancer, lung disease, or muscle inflammation. In addition, given the similarities in perturbed gene expression between skin and muscle tissue, it is likely that analysis of a more readily evaluable target organ such as skin might shed light on mechanisms of disease propagation throughout the body.

  View details for DOI 10.1097/BOR.0b013e3283585748

  View details for PubMedID 22907594