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Comparative Study
. 2013 Feb;22(2):251-60.
doi: 10.1158/1055-9965.EPI-12-1007-T. Epub 2012 Dec 5.

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

Kyle M Walsh  1 , Ivan P Gorlov, Helen M Hansen, Xifeng Wu, Margaret R Spitz, Huifeng Zhang, Emily Y Lu, Angela S Wenzlaff, Jennette D Sison, Chongjuan Wei, Stacy M Lloyd, Wei Chen, Marsha L Frazier, Michael F Seldin, Laura J Bierut, Paige M Bracci, Margaret R Wrensch, Ann G Schwartz, John K Wiencke, Christopher I Amos
Affiliations
Comparative Study

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

Kyle M Walsh et al. Cancer Epidemiol Biomarkers Prev. 2013 Feb.

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 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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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT:

Laura J. Bierut served as a consultant for Pfizer Inc. in 2008 and is an inventor on the patent “Markers for Addiction” (US 20070258898) covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. Other authors do not have any conflicts of interest, financial or otherwise.

Figures

Figure 1
Figure 1. Association of SNP on chromosome 5p15.33 and 6p22.1-p21.31 with lung cancer
(A) Association of 111 directly genotyped SNPs (black) and 305 imputed SNPs (gray) with lung cancer, adjusted for sex, age, study site, % sub-Saharan African ancestry, % European ancestry, and number of pack-years smoked. Triangles denote SNPs which are associated with lung cancer in the NHGRI catalog. (B) Genes in the analyzed region and patterns of LD. Darker shading indicates higher r2 values and greater correlation between the SNPs. (C) Association of 320 directly genotyped SNPs (black) and 36,242 imputed SNPs (gray) with lung cancer, adjusted for sex, age, study site, % sub-Saharan African ancestry, % European ancestry, and number of pack-years smoked. Triangles denote SNPs which are associated with lung cancer in the NHGRI catalog. (D) Patterns of LD in the analyzed region. Darker shading indicates higher r2 values and greater correlation between the SNPs.
Figure 2
Figure 2. Association of SNPs on chromosome 15q25.1 with lung cancer
(A) Association of 242 directly genotyped SNPs (black) and 1,013 imputed SNPs (gray) with lung cancer, adjusted for sex, age, study site, % sub-Saharan African acnestry, % European ancestry, and number of pack-years smoked. Triangles denote SNPs which are associated with lung cancer the NHGRI catalog. (B) Patterns of LD in the analyzed region. Darker shading indicates higher r2 values and greater correlation between the SNPs.
Figure 3
Figure 3. Association of SNPs on chromosome 5p15.33 and 6p21.33 with lung cancer, by histologic subtype
(A) Association of SNPs at 5p15.33 with lung cancer, adjusted for sex, age, study site, % sub-Saharan African ancestry, % European ancestry, and number of pack-years smoked. Circles denote associations for all lung cancer histologies compared to controls. Squares denote associations for adenocarcinoma cases compared to controls. Triangles denote associations for squamous-cell carcinoma cases compared to controls. Crosses denote associations for squamous cell carcinoma cases compared to controls. (B) Association of SNPs at 6p21.33 with lung cancer, adjusted for sex, age, study site, % sub-Saharan African ancestry, % European ancestry, and number of pack-years smoked. Circles denote associations for all lung cancer histologies compared to controls. Squares denote associations for adenocarcinoma cases compared to controls. Triangles denote associations for squamous-cell carcinoma cases compared to controls. Crosses denote associations for squamous cell carcinoma cases compared to controls.
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References

    1. Wang Y, Broderick P, Webb E, Wu X, Vijayakrishnan J, Matakidou A, et al. Common 5p15.33 and 6p21. 33 variants influence lung cancer risk. Nat Genet. 2008;40(12):1407–9. - PMC - PubMed
    1. Landi MT, Chatterjee N, Yu K, Goldin LR, Goldstein AM, Rotunno M, et al. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet. 2009;85(5):679–91. - PMC - PubMed
    1. Broderick P, Wang Y, Vijayakrishnan J, Matakidou A, Spitz MR, Eisen T, et al. Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study. Cancer Res. 2009;69(16):6633–41. - PMC - PubMed
    1. McKay JD, Hung RJ, Gaborieau V, Boffetta P, Chabrier A, Byrnes G, et al. Lung cancer susceptibility locus at 5p15. 33. Nat Genet. 2008;40(12):1404–6. - PMC - PubMed
    1. Hsiung CA, Lan Q, Hong YC, Chen CJ, Hosgood HD, Chang IS, et al. The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia. PLoS Genet. 2010;6(8) - PMC - PubMed

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