Lynch syndrome: influence of additional susceptibility variants on cancer risk

Some patients with Lynch syndrome (LS) have extreme phenotypes, i.e. cancer before the recommended screening age, or cancer for which there are no screening guidelines. We made the hypothesis that additional germline variants in cancer susceptibility genes (CSG) could explain some of these phenotypes. We compared the prevalence of additional CSG variants in LS patients with a cancer diagnosis before age 30 (early-onset, EO group) and after 40 (usual-onset, UO group). While there was no overall difference, we did find an excess of pathogenic variants and variants of unknown significance in EO cases when only gastrointestinal CSG were considered (OR 2.25; 95% CI: 1.01-5.06, p value = 0.04). Four EO cases stood out: two with POLE/POLD1 variants in the key exonuclease domain, one with a BMPR1A duplication and one with an EPCAM deletion. Additional germline variants should be considered in future screening recommendations, as they might influence cancer risk.

Automated summary

Some patients with Lynch syndrome (LS) exhibit extreme phenotypes, such as cancer at an early age or cancer types without screening guidelines. This study investigated the role of additional germline variants in cancer susceptibility genes (CSG) in explaining these phenotypes. Comparison of LS patients with early-onset (EO) and usual-onset (UO) cancer diagnoses revealed an excess of pathogenic variants and variants of unknown significance in the gastrointestinal CSG for the EO group. Notable germline variants were identified, suggesting the consideration of additional variants in future screening recommendations to better assess cancer risk.