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

Abstract

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 × 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.

Polymorphisms in human telomerase reverse transcriptase (h TERT ) gene and susceptibility to gastric cancer in a Turkish population: Hospital-based case–control study

“…We also revealed that carrying TT genotype of hTERT rs2735940 T>C polymorphism had an increased risk of developing GC in codominant, dominant and log-additive inheritance models. Our findings confirm the results of studies, that reported the association of T allele and/or TT genotype of hTERT rs2735940 T>C polymorphism with an increase cancer risk (Pande et al, 2011;Sheng et al, 2013;Choi et al, 2009;Walsh et al, 2013). Similar to this findings, statistically significant increased cancer risk was observed for T allele and/or TT genotype of hTERT rs2735940 T>C polymorphism in meta-analysis with 19385 cancer cases and 17558 controls (Yang et al, 2015).…”

“…The correlation between the hTERT rs2735940 T>C polymorphism and cancer susceptibility has also been controversial such as hTERT rs2736109 G>A polymorphism (Shen et al, 2010;Pande et al, 2011;Savage et al, 2007;Sheng et al, 2013;Choi et al, 2009;Walsh et al, 2013;Yang et al, 2015;Hofer et al, 2012;Iizuka et al, 2013). Choi et al (2009), Pande et al (2011 and Walsh et al (2013) suggested that T allele and/or TT genotype of hTERT rs2735940 T>C polymorphism were significantly associated with the risk of LC in ethnic Koreans, non-Hispanic white subjects and African-American ethnicity respectively.…”

“…Choi et al (2009), Pande et al (2011 and Walsh et al (2013) suggested that T allele and/or TT genotype of hTERT rs2735940 T>C polymorphism were significantly associated with the risk of LC in ethnic Koreans, non-Hispanic white subjects and African-American ethnicity respectively. Sheng et al (2013) found that TT genotype of functional hTERT promoter region polymorphism (rs2735940 T>C) was concerned with risk of childhood ALL in Chinese population.…”

Update in Lung Cancer and Mesothelioma 2012

“…A limitation of several of these GWAS that has been addressed recently is the restriction primarily to white men. Notably, Walsh and colleagues showed in a large multicenter case control study that polymorphisms in three chromosomal regions (5p15.33, 6p21.33, and 15q25.1) were associated with lung cancer risk in African Americans (65). SNPs with select chromosomal loci were associated with specific histological subtypes, with 5p15.33 associated with adenocarcinoma and 6p21.33 with SCC.…”

Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population

“…Studies have been conducted to further interrogate chromosomal regions 2q31.1, 5p15.33, 6p22.1-p21.31, and 15q25.1 in African Americans, including fine mapping studies [27–31]. The 15q25.1 region harbors three nicotinic acetylcholine receptor subunit genes ( CHRNA3 , CHRNA4 , and CHRNA5 ), which are associated with lung cancer [9, 11, 12], smoking behavior [32], nicotine addiction [33], and increased exposure to specific nicotine metabolites [34].…”