Genetic Variants of CLEC4E and BIRC3 in Damage-Associated Molecular Patterns-Related Pathway Genes Predict Non-Small Cell Lung Cancer Survival.

Abstract

Accumulating evidence supports a role of various damage-associated molecular patterns (DAMPs) in progression of lung cancer, but roles of genetic variants of the DAMPs-related pathway genes in lung cancer survival remain unknown. We investigated associations of 18,588 single-nucleotide polymorphisms (SNPs) in 195 DAMPs-related pathway genes with non-small cell lung cancer (NSCLC) survival in a subset of genotyping data for 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another independent subset of genotyping data for 984 patients from Harvard Lung Cancer Susceptibility Study. We performed multivariate Cox proportional hazards regression analysis, followed by expression quantitative trait loci (eQTL) analysis, Kaplan-Meier survival analysis and bioinformatics functional prediction. We identified that two SNPs (i.e., CLEC4E rs10841847 G>A and BIRC3 rs11225211 G>A) were independently associated with NSCLC overall survival, with adjusted allelic hazards ratios of 0.89 (95% confidence interval=0.82-0.95 and P=0.001) and 0.82 (0.73-0.91 and P=0.0003), respectively; so were their combined predictive alleles from discovery and replication datasets (P trend=0.0002 for overall survival). We also found that the CLEC4E rs10841847 A allele was associated with elevated mRNA expression levels in normal lymphoblastoid cells and whole blood cells, while the BIRC3 rs11225211 A allele was associated with increased mRNA expression levels in normal lung tissues. Collectively, these findings indicated that genetic variants of CLEC4E and BIRC3 in the DAMPs-related pathway genes were associated with NSCLC survival, likely by regulating the mRNA expression of the corresponding genes.

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Citation

Published Version (Please cite this version)

10.3389/fonc.2021.717109

Publication Info

Liu, Lihua, Hongliang Liu, Sheng Luo, Edward F Patz, Carolyn Glass, Li Su, Lijuan Lin, David C Christiani, et al. (2021). Genetic Variants of CLEC4E and BIRC3 in Damage-Associated Molecular Patterns-Related Pathway Genes Predict Non-Small Cell Lung Cancer Survival. Front Oncol, 11. p. 717109. 10.3389/fonc.2021.717109 Retrieved from https://hdl.handle.net/10161/23956.

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Scholars@Duke

Luo

Sheng Luo

Professor of Biostatistics & Bioinformatics
Patz

Edward F. Patz

James and Alice Chen Distinguished Professor of Radiology

There are numerous ongoing clinical studies primarily focused on the early detection of cancer.

The basic science investigations in our laboratory concentration on three fundamental translational areas,

1) Development of molecular imaging probes - We have used several different approaches to develop novel imaging probes that characterize and phenotype tumors.

2) Discovery of novel lung cancer biomarkers - We explored the use of proteomics, autoantibodies, and genomics to discover blood and tissue biomarkers for early cancer detection and phenotyping of cancer.

3) Host response to cancer - We study the native immune response to tumors as this may provide cues to relevant diagnostic and therapeutic targets. Most recently we have focused on intratumoral lymphocytes and their specific tumor antigens.

 

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
Director, Duke University Hospital Autopsy Service 
Associate Director, Residency Program  

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 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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