Somatic Mutation Profiles of Colorectal Cancer by Birth Cohort

PURPOSE Incidence rates of early-onset colorectal cancer (CRC) have risen globally, with younger birth cohorts—individuals born after 1960—experiencing higher rates. However, whether somatic mutation profiles vary across birth cohorts remains unclear. This study examines differences in the mutational landscape of CRC by birth cohort. METHODS Colorectal tumors that underwent somatic next-generation sequencing (NGS) for 154-168 genes in an in-house laboratory between 2015 and 2022 were retrospectively identified. Microsatellite instability status was determined by NGS as either microsatellite stable (MSS) or microsatellite instability–high (MSI-H). Patients with hereditary cancer syndromes or inflammatory bowel disease were excluded. Genes were then grouped according to their molecular pathway. Associations between somatic mutations and birth cohorts were assessed using univariable and multivariable logistic regression. Associations were adjusted for CRC stage, location, neoadjuvant chemo/radiotherapy, and age. RESULTS Overall, 369 patients with CRC were identified. The median birth year was 1955 (IQR, 1947-1963) and the median age at diagnosis of CRC was 62.9 (IQR, 52.9-70.8). Twenty (5.4%) had MSI-H tumors and were analyzed separately from MSS tumors. Patients with MSI-H tumors had an earlier birth year than patients with MSS (median 1946 v 1956, P < .001), but this association was not significant after adjusting for confounders ( P = .722). No correlation between tumor mutational burden and birth year was identified after controlling for confounders ( P = .427). There were no statistically significant differences in mutation prevalence or pathway-level alterations by birth cohort. CONCLUSION In this study, mutational landscape of CRC did not differ by birth cohort, suggesting that the observed shifts in CRC incidence across generations are unlikely to be driven by changes in tumor genomics. However, larger studies are needed to validate these findings.