51. Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 Regions Identifies Functional and Histology-Specific Lung Cancer Susceptibility Loci in African-Americans
- Author
-
Walsh, Kyle M, Gorlov, Ivan P, Hansen, Helen M, Wu, Xifeng, Spitz, Margaret R, Zhang, Huifeng, Lu, Emily Y, Wenzlaff, Angela S, Sison, Jennette D, Wei, Chongjuan, Lloyd, Stacy M, Chen, Wei, Frazier, Marsha L, Seldin, Michael F, Bierut, Laura J, Bracci, Paige M, Wrensch, Margaret R, Schwartz, Ann G, Wiencke, John K, and Amos, Christopher I
- Subjects
Epidemiology ,Biomedical and Clinical Sciences ,Health Sciences ,Oncology and Carcinogenesis ,Lung ,Cancer ,Genetics ,Prevention ,Human Genome ,Lung Cancer ,2.1 Biological and endogenous factors ,Adenocarcinoma ,Black or African American ,Aged ,Biomarkers ,Tumor ,Carcinoma ,Squamous Cell ,Case-Control Studies ,Chromosome Mapping ,Chromosomes ,Human ,Pair 15 ,Chromosomes ,Human ,Pair 5 ,Chromosomes ,Human ,Pair 6 ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Linkage Disequilibrium ,Lung Neoplasms ,Male ,Middle Aged ,Nerve Tissue Proteins ,Polymerase Chain Reaction ,Polymorphism ,Single Nucleotide ,Prognosis ,Proteins ,Receptors ,Nicotinic ,Risk Factors ,Small Cell Lung Carcinoma ,Telomerase ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundGenome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31, and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans and refined previous association signals by using the reduced linkage disequilibrium observed in African-Americans.Methods1,308 African-American cases and 1,241 African-American controls from 3 centers were genotyped for 760 single-nucleotide polymorphisms (SNP) spanning 3 regions, and additional SNP imputation was carried out. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate.ResultsThe strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution [rs16969968: OR, 1.57; 95% confidence interval (CI), 1.25-1.97; P, 1.1 × 10(-4)) and variants in the 5'-UTR. Associations on 6p22.1-p21.31 were histology specific and included a missense variant in BAT2 associated with squamous cell carcinoma (rs2736158: OR, 0.64; 95% CI, 0.48-0.85; P, 1.82 × 10(-3)). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR, 0.82; 95% CI, 0.73-0.93; P, 1.1 × 10(-3)). This association was stronger among cases with adenocarcinoma (OR, 0.75; 95% CI, 0.65-0.86; P, 8.1 × 10(-5)).ConclusionsPolymorphisms in 5p15.33, 6p22.1-p21.31, and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous cell carcinoma.ImpactResults implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies.
- Published
- 2013