Background and aims: In the general population, the incidence of early onset colorectal cancer (CRC), defined as diagnosis before age 50, is rising, and a birth cohort effect has been observed in that younger generations have higher CRC incidence compared to older generations. Whether hereditary cancer syndromes that predispose to CRC, such as Lynch syndrome, follow similar birth cohort trends as the general population has not been explored previously. The aim of this study was to evaluate birth cohort effects on age of CRC in Lynch syndrome patients.
Methods: Lynch syndrome patients, defined by having a pathogenic or likely pathogenic variant in a mismatch repair gene (MLH1, MSH2, MSH6, PMS2 and EPCAM) were identified from an academic registry between 1990-2023. Demographics, genetic data and cancer incidence were collected. Kaplan-Meier curves were used to assess the age of cancer incidence by birth cohorts, and Cox regression was used to adjust for confounders. Analyses were performed separately for each Lynch syndrome-associated gene.
Results: In total, 151 Lynch syndrome patients were identified. Clinical characteristics are shown in Table 1. Earlier age onset of CRC was noted by birth cohort (Figure 1A), and between those born before or after 1970 (Figure 1B). When the Lynch syndrome genes were analyzed individually, significant differences between those born before or after 1970 were found for MSH2 and PMS2 carriers, while results were borderline for MLH1 carriers and not significant for MSH6 carriers (Figure 1C-F). Using Cox regression to adjust for stage of CRC, birth year and proband status, later birth year was noted to be the only significant predictor for earlier age CRC (HR 1.20, 95% CI 1.14-1.26). Exclusion of probands, to control for ascertainment bias, resulted in similar findings, as non-probands born in later generations were more likely to develop earlier age CRC (HR 1.11 95% CI 1.02-1.21). There were no significant differences between birth cohorts and extra-colonic malignancies (p=0.354).
Conclusions: Younger birth cohorts of Lynch syndrome patients appear to develop CRC at earlier ages compared to older birth cohorts similar to trends observed in the general population. Interestingly, results were not uniform across all Lynch syndrome genes and warrants further evaluation. Larger studies are needed to validate these results and to further control for ascertainment bias and possibly genetic anticipation.

Dezheng Huo

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