Novel variants of ELP2 and PIAS1 in the interferon gamma signaling pathway are associated with non-small cell lung cancer survival.

Abstract

BACKGROUND:Interferon gamma (IFNγ) is a pleiotropic cytokine that plays critical immunomodulatory roles in intercellular communication in innate and adaptive immune responses. Despite recognition of IFNγ signaling effects on host defense against viral infection and its utility in immunotherapy and tumor progression, the roles of genetic variants of the IFNγ signaling pathway genes in cancer patient survival remain unknown. METHODS:We used a discovery genotyping dataset from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (n=1,185) and a replication genotyping dataset from the Harvard Lung Cancer Susceptibility Study (n=984) to evaluate associations between 14,553 genetic variants in 150 IFNγ pathway genes and survival of non-small cell lung cancer (NSCLC). RESULTS:The combined analysis identified two independent potentially functional single-nucleotide polymorphisms (SNPs), ELP2 rs7242481G>A and PIAS1 rs1049493T>C, to be significantly associated with NSCLC survival, with a combined hazards ratio (HR) of 0.85 [95% CI= 0.78-0.92, P<0.0001] and 0.87 (0.81-0.93, P<0.0001), respectively. Expression quantitative trait loci analyses showed that the survival-associated ELP2 rs7242481A allele was significantly associated with increased mRNA expression levels of ELP2 in 373 lymphoblastoid cell lines and 369 whole blood samples. The PIAS1 rs1049493C allele was significantly associated with decreased mRNA expression levels of PIAS1 in 383 normal lung tissues and 369 whole blood samples. CONCLUSIONS:Genetic variants of IFNγ signaling genes are potential prognostic markers for NSCLC survival, likely through modulating the expression of key genes involved in host immune response. IMPACT:Once validated, these variants could be useful predictors of NSCLC survival.

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Published Version (Please cite this version)

10.1158/1055-9965.epi-19-1450

Publication Info

Zhao, Yu Chen, Dongfang Tang, Sen Yang, Hongliang Liu, Sheng Luo, Thomas E Stinchcombe, Carolyn Glass, Li Su, et al. (2020). Novel variants of ELP2 and PIAS1 in the interferon gamma signaling pathway are associated with non-small cell lung cancer survival. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. pp. cebp.1450.2019–cebp.1450.2019. 10.1158/1055-9965.epi-19-1450 Retrieved from https://hdl.handle.net/10161/21103.

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Scholars@Duke

Luo

Sheng Luo

Professor of Biostatistics & Bioinformatics
Glass

Carolyn Glass

Associate Professor of Pathology

Cardiothoracic Pathologist and Physician-Scientist
Division Chief, Cardiovascular Pathology 
Co-Director, Division of Artificial Intelligence and Computational Pathology
Associate Director, Residency Program  
Director, Duke University Hospital Autopsy Service 

Dr. Glass completed medical residency in Anatomic Pathology at the Brigham and Women’s Hospital/Harvard Medical School followed by fellowships in Cardiothoracic Pathology also at Brigham and Women’s Hospital/Harvard Medical School and Pulmonary/Cardiac Transplant Pathology at the University of Texas Southwestern Medical Center. Dr. Glass initially trained as a vascular surgeon with a focus on endovascular/interventional procedures through the 0+5 Integrated Vascular Surgery Program at the University of Rochester Medical Center from 2007-2011.  As a recipient of the NIH National Lung Blood Institute T32 Ruth Kirschstein National Service Research Award, she completed a Ph.D with a concentration in Genomics and Epigenetics in 2014.

Dr. Glass was awarded a five-year $3.2 million NIH grant to serve as P.I. of the Pathology Core as part of a larger U54 NIH grant ($13.5 million along with Duke Department of Medicine) to establish a Senescent Cell Human Tissue Mapping Center as part of the NIH Cellular Senescence Network. As a thoracic pathologist, Dr. Glass also has a special interest in identifying new epigenetic biomarkers that may predict response or resistance to conventional, targeted and immune therapy using computational techniques. She works closely with the Duke Thoracic Oncology Group, DCI Center for Cancer Immunotherapy, Duke Division of Cardiovascular Medicine and Cardiothoracic Surgery and Pratt School of Biomedical Engineering. 

Dr. Glass is the recipient of the Society of Cardiovascular Pathology (SCVP) Young Investigator’s Award, the William von Liebig Vascular Biology Research Fellowship at the Harvard Institutes of Medicine, the Duke Pathology Salvatore V. Pizzo Faculty Research Mentor Award, the Duke Department of Pathology Early Career Research Achievement Award and is author of over 90 publications (including book chapters in the recent W.H.O. Classification Tumours of the Lung, Pleura, Thymus and Heart) and 50 national presentations in cardiovascular disease, thoracic malignancies, surgery and machine learning. 

In addition to her clinical and research activities, Dr. Glass serves on the Executive/National Committees for the Society of Cardiovascular Pathology, College of American Pathology Artificial Intelligence Committee and the Duke School of Medicine Executive Admissions Committee. 




Wei

Qingyi Wei

Professor Emeritus in Population Health Sciences

Qingyi Wei, MD, PhD, Professor in the Department of Medicine, is Associate Director for Cancer Control and Population Sciences, Co-leader of CCPS and Co-leader of Epidemiology and Population Genomics (Focus Area 1). He is a professor of Medicine and an internationally recognized epidemiologist focused on the molecular and genetic epidemiology of head and neck cancers, lung cancer, and melanoma. His research focuses on biomarkers and genetic determinants for the DNA repair deficient phenotype and variations in cell death. He is Editor-in-Chief of the open access journal "Cancer Medicine" and Associate Editor-in-Chief of the International Journal of Molecular Epidemiology and Genetics.

Area of Expertise: Epidemiology


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