APOB Genotypes and CDH13 Haplotypes in the Cholesterol-Related Pathway Genes Predict Non-Small Cell Lung Cancer Survival.

Abstract

BACKGROUND:Several oncogenic signals are involved in the synthesis, metabolism, transportation, and modulation of cholesterol. However, the roles of genetic variants of the cholesterol pathway genes in cancer survival remain unclear. METHODS:We investigated associations between 26,781 common SNPs in 209 genes of the cholesterol pathway and non-small cell lung cancer (NSCLC) survival by utilizing genotyping data from two published genome-wide association studies. We used multivariate Cox proportional hazards regression and expression quantitative trait loci analyses to identify survival-associated SNPs and their correlations with the corresponding mRNA expression, respectively. We also used the Kaplan-Meier survival analysis and bioinformatics functional prediction to further evaluate the identified independent SNPs. RESULTS:We found five independent SNPs (APOB rs1801701C>T; CDH13 rs35859010 C>T, rs1833970 T>A, rs254315 T>C, and rs425904 T>C) to be significantly associated with NSCLC survival in both discovery and replication datasets. When the unfavorable genotype (APOB rs1801701CC) and haplotypes (CDH13 rs35859010-rs1833970-rs254315-rs425904 C-A-T-C and T-T-T-T) were combined into a genetic score as the number of unfavorable genotypes/haplotypes (NUGH) in the multivariate analysis, an increased NUGH was associated with worse survival (P trend < 0.0001). In addition, both APOB rs1801701T<C and CDH13 rs425904C<T were correlated with mRNA expression of the genes in normal lung tissues from the genotype-tissue expression project. CONCLUSIONS:Genetic variants of APOB and CDH13 in the cholesterol pathway were associated with NSCLC survival, possibly by affecting their gene expression. IMPACT:Genetic variants of APOB and CDH13 in the cholesterol pathway may provide new scientific insights into NSCLC prognosis.

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Published Version (Please cite this version)

10.1158/1055-9965.epi-19-1262

Publication Info

Deng, Wei, Hongliang Liu, Sheng Luo, Jeffrey Clarke, Carolyn Glass, Li Su, Lijuan Lin, David C Christiani, et al. (2020). APOB Genotypes and CDH13 Haplotypes in the Cholesterol-Related Pathway Genes Predict 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. 10.1158/1055-9965.epi-19-1262 Retrieved from https://hdl.handle.net/10161/20709.

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Scholars@Duke

Luo

Sheng Luo

Professor of Biostatistics & Bioinformatics
Clarke

Jeffrey Melson Clarke

Associate Professor of Medicine
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. 





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