Pathogenic germline variants in patients with early-onset colorectal cancer according to phenotype.

We assessed retrospectively the prevalence of pathogenic germline variants (PGVs) in 271 French adult patients diagnosed with colorectal cancer (CRC) before age 41, stratified by phenotype. APC, BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH3, MSH6, MUTYH, POLE, POLD1, PTEN, PMS2, SMAD4, and STK11 were analysed. Overall, 21.4% of cases carried a PGV. A high prevalence was observed in Mismatch Repair-deficient (MMRd) CRC (59.7%, MMR genes) and CRC associated with polyposis (48%, APC , biallelic MUTYH and MSH3 , POLE ). In contrast, MMR-proficient, non-polyposis cases only had a 1.7% prevalence. The only gene involved in this third group was POLE , and two out of three cases had either two synchronous CRC or a CRC family history. PGV prevalence is dependent on CRC phenotype, questioning the need for systematic germline testing in early-onset cases. A more targeted approach, focusing on MMRd CRC, or CRC associated with polyposis, might be warranted.