Novel genetic variants in KIF16B and NEDD4L in the endosome-related genes are associated with non-small cell lung cancer survival.
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2019-10-16
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The endosome is a membrane-bound organ inside most eukaryotic cells, playing an important role in adaptive immunity by delivering endocytosed antigens to both MHC class I and II pathways. Here, by analyzing two published genome-wide association studies (GWASs), we evaluated associations between genetic variants in the endosome-related gene-set and survival of patients with non-small cell lung cancer (NSCLC). The discovery included 44,112 (3,478 genotyped and 40,634 imputed) single-nucleotide polymorphisms (SNPs) in 220 genes in a single locus analysis for their associations with survival of 1,185 NSCLC patients from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. After validation of the 821 survival-associated significant SNPs in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility study, 14 SNPs remained significant. The final multivariate stepwise Cox proportional hazards regression model in the PLCO datasets identified three potentially functional and independent SNPs (KIF16B rs1555195 C>T, NEDD4L rs11660748 A>G and rs73440898 A>G) with an adjusted hazards ratio (HR) of 0.86 [95% confidence interval (CI)=0.79-0.94, P=0.0007], 1.31 (1.16-1.47, P=6.0×10-5 ) and 1.27 (1.12-1.44, P=0.0001) for overall survival (OS), respectively. Combined analysis of the adverse genotypes of these three SNPs revealed a trend in the genotype-survival association (Ptrend <0.0001 for OS and Ptrend <0.0001 for disease-specific survival). Furthermore, the survival-associated KIF16B rs1555195T allele was significantly associated with decreased mRNA expression levels of KIF16B in both lung tissues and blood cells. Therefore, genetic variants of the endosome-related genes may be biomarker for NSCLC survival, possibly through modulating the expression of corresponding genes. This article is protected by copyright. All rights reserved.
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Yang, Sen, Dongfang Tang, Yu C Zhao, Hongliang Liu, Sheng Luo, Thomas E Stinchcombe, Carolyn Glass, Li Su, et al. (2019). Novel genetic variants in KIF16B and NEDD4L in the endosome-related genes are associated with non-small cell lung cancer survival. International journal of cancer. 10.1002/ijc.32739 Retrieved from https://hdl.handle.net/10161/19676.
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Sheng Luo
Carolyn Glass
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 serves as P.I. of multiple NIH grants, including U54 and SBIR. 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.
Qingyi Wei
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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