Abstract C016: Genomic analysis of patients across continental ancestry groups

Abstract People with different ancestries inherit different risks and encounter different environmental exposures resulting in different somatic profiles. A lack of knowledge about ancestry-specific alterations is a major barrier to implementing precision medicine, leading to inequities in genetic testing, targeted treatment and clinical trial design for cancer patients from the underserved populations. However, a limited number of cancer cases from non-European populations have been sequenced in research setting, and paired normal samples are often not collected in routine clinical care. Here, we inferred African (AFR), South Asian (SAS), East Asian (EAS), American (AMR) and European (EUR) ancestry from comprehensive genomic profiling (CGP) of over 200,000 tumors at Foundation Medicine and identified 18717, 8588, 6594 patients with significant proportions of AFR, AMR, EAS ancestry, respectively. Using logistic regressions with age of diagnosis, gender and tumor mutation burden (TMB) as covariates, we identified 165 ancestry-associated genes across 14 common cancer types. We found that in colorectal cancer, KRAS (OR=1.5, FDR corrected p=4x10-44) and APC (OR=1.4, FDR corrected p=1x10-16) mutations were enriched in patients with AFR ancestry, whereas BRAF mutations were depleted in both AFR (OR=0.5, FDR corrected p=5x10-24) and EAS (OR=0.6, FDR corrected p=6x10-5) patients. CDK12 mutations were enriched in both AFR (OR=1.6, FDR corrected p=2x10-4) and EAS (OR=3.1, FDR corrected p=2x10-7) prostate cancer patients. For patients with AMR ancestry, increased mutation frequency was observed in SETD2 in pancreatic cancer (OR=3.4, FDR corrected p=1x10-4), and VHL in renal clear cell carcinoma (OR=1.9, FDR corrected p=2x10-4). For renal cell carcinoma patients with AFR ancestry, mutations in NF2 were enriched (OR=2.5, FDR =8x10-6). In GBM, TERT alterations were associated with EUR ancestry (OR=1.3, FDR corrected p=0.003). Interestingly, TMB-high status was associated with EUR ancestry in melanoma (OR=5.9, p=6x10-36) and anti-correlated with AFR ancestry in endometrial carcinoma (OR=0.7, p=1x10-6). Our large-scale ancestry analysis characterized the somatic landscape of non-European cancer patients. Future directions include quantifying the germline heritability of identified ancestry-associated mutations using a local ancestry risk score (LRS). Citation Format: Jian Carrot-Zhang, Justin New, Amy Xie, Garrett Frampton. Genomic analysis of patients across continental ancestry groups [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C016.