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
Cette étude américaine (1 308 cas et 1 241 témoins) évalue l'association entre des polymorphimes à simple nucléotide situés dans trois régions chromosomiques et le risque de cancer du poumon chez une population afro-américaine
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 refined previous association signals by utilizing the reduced linkage disequilibrium observed in African-Americans. Methods: 1308 African-American cases and 1241 African-American controls from three centers were genotyped for 760 single nucleotide polymorphisms spanning three regions, and additional SNP imputation was performed. 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% CI = 1.25-1.97, P = 1.1 x 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 x 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 x 10-3). This association was stronger among cases with adenocarcinoma (OR = 0.75, 95% CI = 0.65-0.86, P = 8.1 x 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.