Common Genetic Variants Within Tep1 Gene (14q11.2 Locus) And Tk1 Gene (17q25.3 Locus) Are Associated With The Risk Of Colorectal Tumors In Latinos

Introduction: Around 63 common risk variants have been associated with colorectal cancer (CRC) through genome-wide association studies (GWAS) in European and Asian populations; these variants, together with the high penetrance genes responsible for 5% of the cases, do not completely explain the CRC heritability estimated at ~ 35%. Objective: To discover new common variants associated with the risk of colorectal tumors, taking advantage of the high level of admixture in Latino populations. Materials and methods: We performed a candidate gene association (CG) and GWAS analyses, in a multicenter case-control study that included 313 cases of CRC, 200 cases of adenomatous polyps (AP) and 506 controls from six Colombian cities. The role of these common variants was assessed by basic SNP association analyses (X2) and logistic regressions adjusted for age, sex and ancestry proportions. Selected SNPs were genotyped by TaqMan in additional samples. Results: European ancestry was associated with the risk of AP while African ancestry was associated with the risk of both, AP and CCR, (P ≤ 0.01). In the adjusted logistic regression analyses of the CG study, we found that the minor allele (A) of the SNP 14q11.2:rs1760898 (C>A) was associated with the risk of CRC (OR 0.48; 95% CI 0.33-0.69; UNADJ P = 6.8 x 10-5; 100,000 Pperm = 0.03). This association persisted in the adjusted logistic regressions analyses with additional samples genotyped by TaqMan (P = 0.03). In the basic SNP association analyses (X2) of the GWAS study, we found that the minor allele (A) of the SNP 17q25.3:rs1065768 (G>A) was associated with the risk of AP (OR 0.35; 95% CI 0.24 -0.51; UNADJ P = 3.4 x 10-8; Bonferroni corrected P = 0.02). This association persisted after including additional samples genotyped by TaqMan, both, in the basic SNP analysis (P = 1.7 x 10-7) and in the adjusted logistic regressions analysis (P = 9.7 x 10-5). Moreover, the association remained when other variables were also included in the model, such as the first 10 major principal components of genetic variability, ancestry proportions along chromosome 17 and locus-specific ancestry (P = 1.7 x 10-4). Conclusions: The SNP rs1760898 (TEP1, Telomerase Associated Protein 1 gene) confers a change of Asparagine (Asn) to Lysine (Lys) within the RNA binding domain, TROVE. This change could affect the activity of telomerase enzyme that has an important role in cancer development. The SNP rs1065768 (39UTR TK1, Thymidine kinase 1 gene) could affect mRNA stability and protein production of TK1, which is essential in DNA synthesis. Although, functional analyses are required to confirm their potential role in colorectal tumorogenesis, our findings help increase our understanding about the biological basis for the development of colorectal tumors, as well as will contribute to the overall knowledge on the heritability of CRC. Citation Format: Maria Carolina Sanabria-Salas, Konrad Rawlik, Albert Tenesa, Adriana Umana-Perez, Martha Lucia Serrano-Lopez, Myriam Sanchez de Gomez, Jovanny Zabaleta, Gustavo Hernandez-Suarez. Common genetic variants within TEP1 gene (14q11.2 locus) and TK1 gene (17q25.3 locus) are associated with the risk of colorectal tumors in Latinos [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-162. doi:10.1158/1538-7445.AM2017-LB-162