Abstract A37: Genome-wide association study of colorectal tumors in Latin American individuals from Colombia

Abstract

Abstract Introduction: Colorectal cancer (CRC) is one of the most common cancers worldwide, with higher incidence among more developed countries. However, mortality rates are higher and increasing in less-developed regions, including Colombia. Incidence and mortality rates of CRC vary across the country, with the lowest rates among populations with increased concentration of Native Americans. Our group previously reported that increased European and African ancestry was associated with higher adenomatous polyps (AP) and CRC risk in Colombians. Based on this observation we hypothesize that genetic contribution to the observed regional variation on CRC development in Colombia might be partly explained by the influence of genetic variants with different frequency distribution in the European, Amerindian, and African ancestral components. Objective: To test our hypothesis we performed a genome-wide association study (GWAS) of colorectal tumors in Colombian CRC and AP cases and controls. Materials and Methods: We conducted a GWAS of Colombians from different regions of the country that included 162 CRC cases, 122 AP cases, and 131 controls. Only SNPs with MAF ≥ 0.05 were included. The role of these common variants was assessed by logistic regression models adjusted for age, sex, and the first 10 principal components (PCs) of the genetic variation. Analyses were performed for a total of 606410 SNPs. The P value threshold for genome-wide significant SNPs was set at the traditional value of ≤ 5 × 10−8. Results: We replicated some of the previously reported associations (8 out of 44 SNPs, P ≤ 0.05) of which 7 had directionally concordant ORs. Regarding the remaining 36 published risk variants, 25 had directionally concordant ORs, even though neither of them was significant at nominal P ≤ 0.05. None of the SNPs analyzed passed the threshold for genome-wide significance. However, we found multiple suggestive associations. One novel SNP within the region 2q11.2-q12 near the gene MAP4K4 was associated with the risk of AP (rs4280476-G; OR 0.36; 95% CI 0.23-0.56; P = 8.7 x 10-6). We also found four novel SNPs across three regions with suggestive CRC risk associations: rs10514122-A located in the locus 5q14 near the TBCA gene (OR 0.30; 95% CI 0.18-0.49; P = 3.6 x 10-6), rs10746883-G (OR 0.37; 95% CI 0.25-0.56; P = 3.2 x 10-6) and the rs10781032-A (OR 0.35; 95% CI 0.22-0.53; P = 1.7 x 10-6), in high LD with each other (R2 = 0.81), located in the locus 9q21.1-q21.2 near the genes TRPM3 and TMEM2 and the SNP rs2800641-G located in the region 6q25.2 near the MYCT1 gene (OR 2.96; 95% CI 1.83-4.77; P = 8.9 x 10-6). The inflation factors (λ), when comparing AP or CRC cases vs controls, were 1.05 and 1.04, respectively, indicating appropriate control for population stratification. Finally, it is of note that the MAF reported for the 5 novel SNPs identified in our study shows important differences between European, Asian, and African reference populations from the public database 1,000 genomes. Conclusions: In this GWAS of AP and CRC in individuals from Colombia, we replicated some of the previously reported associations and identified suggestive signals for 5 novel risk alleles located at four loci (2q11.2-q12, 5q14, 9q21.1-q21.2, and 6q25.2). Further work is needed to replicate our findings in other Latin American populations. Citation Format: Maria Carolina Sanabria-Salas, Laura Fejerman, Konrad Rawlik, Albert Tenesa, Martha L. Serrano-Lopez, Jovanny Zabaleta, Gustavo A. Hernandez-Suarez. Genome-wide association study of colorectal tumors in Latin American individuals from Colombia [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A37.