Genetic Ancestry And Somatic Mutational Frequencies In Colorectal Cancer: Findings From The Latino Colorectal Cancer Consortium

Subgroups of Hispanics/Latinos (HL) experience up to 30% higher colorectal cancer (CRC) mortality than non-Hispanic Whites. This disparity is not fully explained by socio-demographics or access to care, suggesting that biology plays a role. However, biological factors have been underexplored, in part due to a lack of diversity in available datasets. To address this limitation, we established the Latino Colorectal Cancer Consortium (LC3) and examined the association between genetic ancestry and somatic mutation frequencies in HL and in non-HL from Total Cancer Care (Moffitt Cancer Center). We hypothesized that ancestral haplotypes that vary across racial/ethnic populations contribute to differential somatic mutational profiles. We identified 321 primary CRC cases (34% HL (majority of Mexican and Puerto Rican origin), 63% non-HL, 3% unknown) and whole exome sequencing data. Somatic mutations were called from tumor/normal pairs using a bioinformatic pipeline including Burrows-Wheeler Aligner, the Genome Analysis Toolkit (GATK), MuTect, and Strelka. High quality mutation calls were filtered to exclude variants at ≥1% in 1000 Genomes. Inherited variants for ancestry analysis were called using GATK. Global proportions of African (AFR), Asian (ASN), European (EUR), and Indigenous American (IA) ancestry were estimated using ADMIXTURE with exome-wide SNPs overlapping 1000 Genomes. The associations between genetic ancestry and somatic mutation status in 38 genes commonly over-mutated in CRC were examined using compositional analysis in the context of logistic regression. Among HL, ancestry proportions were: AFR (mean: 0.15; range: 2 × 10−03-0.63), ASN (0.07; 0.02-0.92), EUR (0.56, 0.08-0.85) and IA (0.22, 3 × 10−03-0.64). Among non-HL, they were: AFR (0.03; 1 × 10−05-0.83), ASN (0.10; 0.01-0.70), EUR (0.85, 0.13-0.93) and IA (0.02, 2 × 10−03-0.65). Genetic ancestry was associated with the presence of any mutation in MSH3 (P=0.014), ACVR1B (P=0.016) or BRAF (P=0.016); or specifically, with the presence of any truncating mutation in TGFBR2 (P=0.018) or ACVR1B (P=0.024). Relative to EUR ancestry, individuals with higher IA ancestry had a lower probability of any BRAF mutation (OR (95% CI)=0.72 (0.55-0.94); P=0.015) and a higher probability of an APC truncating mutation (1.17 (1.00-1.36); P=0.053). In contrast, higher AFR ancestry (relative to EUR) was associated with increased odds of ACVR1B (OR (95% CI)=1.27 (1.02-1.58); P=0.033) or NRAS mutations (1.22 (1.00-1.47); P=0.047) and decreased odds of an FBXW7 mutation (0.87 (0.77-0.98); P=0.023). Our findings from the largest study of CRC somatic landscapes in HL provide early evidence of mutation frequency differences in driver genes associated with genetic ancestry. Our ongoing efforts to expand LC3 will inform the development of ancestry-tailored treatment strategies to benefit diverse populations. Citation Format: Marco Matejcic, Jamie K. Teer, Hannah J. Hoehn, Zhihua Chen, Diana B. Diaz, Nathalie Nguyen, Douglas Cress, Estrella Carballido, Jason Fleming, Domenico Coppola, Mariana C. Stern, Brooke L. Fridley, Jane C. Figueiredo, Stephanie L. Schmit. Genetic ancestry and somatic mutational frequencies in colorectal cancer: Findings from the Latino Colorectal Cancer Consortium [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1192.