TY - JOUR
T1 - 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
AU - Walsh, Kyle M.
AU - Gorlov, Ivan P.
AU - Hansen, Helen M.
AU - Wu, Xifeng
AU - Spitz, Margaret R.
AU - Zhang, Huifeng
AU - Lu, Emily Y.
AU - Wenzlaff, Angela S.
AU - Sison, Jennette D.
AU - Wei, Chongjuan
AU - Lloyd, Stacy M.
AU - Chen, Wei
AU - Frazier, Marsha L.
AU - Seldin, Michael F.
AU - Bierut, Laura J.
AU - Bracci, Paige M.
AU - Wrensch, Margaret R.
AU - Schwartz, Ann G.
AU - Wiencke, John K.
AU - Amos, Christopher I.
PY - 2013/2
Y1 - 2013/2
N2 - Background: Genome-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. Methods: 1,308 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. Results: The 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). Conclusions: Polymorphisms 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. Impact: Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies.
AB - Background: Genome-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. Methods: 1,308 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. Results: The 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). Conclusions: Polymorphisms 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. Impact: Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies.
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U2 - 10.1158/1055-9965.EPI-12-1007-T
DO - 10.1158/1055-9965.EPI-12-1007-T
M3 - Article
C2 - 23221128
AN - SCOPUS:84873326172
SN - 1055-9965
VL - 22
SP - 251
EP - 260
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
IS - 2
ER -