Abstract 6816: Germline genetic impact on risk of colorectal cancer according to birth cohorts

Abstract Background: The incidence of colorectal cancer (CRC) has been rising globally among adults aged under 50 years, particularly those born after the 1950s. We hypothesized that the polygenic risk score (PRS) may show stronger associations with CRC risk in more recent birth cohorts, reflecting interactions between genetic susceptibility and increasingly prevalent life-time environmental exposures such as obesity and sedentary behaviors. Methods: Among 37,313 CRC cases and 35,891 controls with available birth year information and genetically defined European ancestry from the Genetics and Epidemiology of Colorectal Cancer Consortium, we calculated the PRS as the weighted sum of risk alleles across 205 CRC-associated genetic variants identified so far. We used multivariable logistic models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of CRC risk associated with PRS across different birth cohorts. We assessed the interaction between PRS and birth cohorts using Wald test and performed subgroup analysis according to age at diagnosis, family history, endoscopic screening, and CRC molecular subtypes. Results: PRS showed a generally stronger association with risk of CRC across successive birth cohorts (p for interaction = 0.005). The OR for CRC per 1-standard deviation increase in PRS was 1.62 (95% CI: 1.48, 1.78) among individuals born before 1920, 1.55 (1.49, 1.60) for 1920-1929, 1.60 (1.55, 1.65) for 1930-1939, 1.67 (1.61, 1.74) for 1940-1949, 1.64 (1.55, 1.73) for 1950-1959, and 1.79 (1.65, 1.95) for those born in 1960 or later. The birth cohort effect was primarily observed among participants without a first-degree family history of CRC, with ORs of 1.62 (1.45, 1.80) for those born before 1920 and 1.91 (1.73, 2.12) for 1960 or later (p for interaction <0.001). The birth cohort effect did not differ by age at diagnosis or history of screening. Across CRC subsites, the birth cohort effect was observed for distal (p for interaction = 0.003) and rectal CRC (p = 0.002) but not proximal CRC (p = 0.82). For tumor molecular subtypes, we observed no interactions between PRS and birth cohorts for subtypes classified by microsatellite instability, BRAF and KRAS mutations, or CpG island methylator phenotype, although only 9.7-12.3% CRC cases had molecular data, limiting statistical power. Conclusions: PRS is more strongly associated with CRC risk in more recent birth cohorts, suggesting the role of gene-environment interaction in the rise in early-onset CRC and highlighting the increasing utility of genetic risk stratification in contemporary populations. Citation Format: Xinyu Wang, Constance Turman, Yufeng Chen, Conghui Qu, Li Hsu, William J. Gauderman, John D. Potter, Ulrike Peters, Mingyang Song. Germline genetic impact on risk of colorectal cancer according to birth cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6816.