Comparison of colorectal cancer (CRC) characteristics across genetic ancestries: Implications for early cancer detection (ECD).

Abstract

164 Background: Blood-based ECD has the potential to reduce mortality rates by improving strategies for, adoption of, and adherence to screening. A deeper understanding of the cancer genomic landscape across genetic ancestries will aid comparable detection performance across a broad population. We evaluated the mutational landscape in patients with CRC across genetic ancestries. Methods: 16,080 de-identified patients with stage I-IV CRC who had personalized, tumor-informed commercial ctDNA testing (Signatera) based on whole exome sequencing (WES) were included. Genetic ancestry determined via supervised local ancestry inference (pmid36042219) included African (AFR), East Asian (EAS), European (EUR), Latino (LAT), and South Asian (SAS). Patients assigned to a single ancestry were included (except SAS due to small cohort size). Somatic single nucleotide variants called from WES were used for mutational signature inference. EUR was the reference group for standard statistical tests with corrections for multiple hypothesis testing. Results: A single genomic ancestry was assigned for 16,257 (99.2%) patients (AFR n=1697, 10%; EAS n=2247, 14%; EUR n=10,526, 64%; LAT n=1291, 1%; SAS n=184, 1%). Across AFR, EAS, EUR, and LAT, approximately half of patients were male (range, 47-54%) and most were aged >50 years. Microsatellite instability (MSI) rates were significantly higher in EUR (14.5%) v AFR (11%, p<0.001), EAS (8%, p<0.001), and LAT (11%, p=0.002). Compared to EUR (range 0.027-875.1 mut/Mb), the distribution of TMB was significantly higher in EAS (0.304-906.2 mut/Mb, p<0.001) and lower in LAT (0.053-476.7 mut/Mb, p<0.001). The POLE hyper-mutator signature was seen in 1.2% of all patients and in 7.6% of all hyper-mutated cases. Patients with the POLE signature were less common in EUR (1.1%) v AFR (2%, p=0.001). There were significant differences in the frequency of driver mutations in APC, BRAF, KRAS, TP53, and PIK3CA between EUR and the other ancestry groups in both MSI and MSS tumors (Table). Median exposure levels to alkylation were higher in EAS v EUR. Conclusions: These data confirm previous results in AFR populations, and reveal novel differences in the EAS and LAT populations. Findings from this study may provide information for developing risk stratification and prevention strategies for the early detection of cancer and provide rationale for precision treatment based on ancestry. [Table: see text]