Pathogenic germline variants in patients with early-onset colorectal cancer according to phenotype. - National Genomics Data Center (CNCB-NGDC)

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

Antoine Dardenne, Marion Dhooge, No��mie Basset, Albain Chansavang, Julie Metras, Solenne Farelly, Jeanne Netter, Florence Coulet, Patrick R Benusiglio

Author Information

Antoine Dardenne: Sorbonne Universit��, Service de Chirurgie digestive, H��pital Saint-Antoine, APHP, Paris, France.
Marion Dhooge: Paris Cit�� Universit��, Service de Gastroent��rologie et Oncologie digestive, UF d'Oncog��n��tique digestive, H��pital Cochin, APHP, Paris, France. ORCID
No��mie Basset: Sorbonne Universit��, H��pital Piti��-Salp��tri��re, D��partement de G��n��tique m��dicale, APHP, Paris, France.
Albain Chansavang: D��partement de M��decine G��nomique des Tumeurs et Cancers, H��pital Cochin, APHP, Universit�� Paris Cit��, Paris, France. ORCID
Julie Metras: Sorbonne Universit��, Service de Chirurgie digestive, H��pital Saint-Antoine, APHP, Paris, France.
Solenne Farelly: Paris Cit�� Universit��, Service de Gastroent��rologie et Oncologie digestive, UF d'Oncog��n��tique digestive, H��pital Cochin, APHP, Paris, France.
Jeanne Netter: Sorbonne Universit��, Service de Chirurgie digestive, H��pital Saint-Antoine, APHP, Paris, France.
Florence Coulet: Sorbonne Universit��, H��pital Piti��-Salp��tri��re, D��partement de G��n��tique m��dicale, APHP, Paris, France.
Patrick R Benusiglio: Sorbonne Universit��, Service de Chirurgie digestive, H��pital Saint-Antoine, APHP, Paris, France. patrick.benusiglio@aphp.fr. ORCID

PMID: 40097831 DOI: 10.1038/s41431-025-01808-x

We assessed retrospectively the prevalence of pathogenic germline variants (PGV) in 268 French adult patients diagnosed with colorectal cancer (CRC) before age 41, stratified by phenotype. APC, BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH3, MSH6, MUTYH, NTHL1, POLE, POLD1, PTEN, PMS2, SMAD4, STK11 and TP53 were analyzed. Overall, 21.6% of cases carried a PGV. A high prevalence was observed in Mismatch Repair-deficient (MMRd) CRC (60.1%, MMR genes) and polyposis-associated CRC (48%, APC, MUTYH and MSH3-biallelic, POLE). Only 2.3% of patients with MMR proficient and without polyposis carried a PGV. The genes involved in this third group were POLE and MSH2, and three out of four cases had either two synchronous CRC or a CRC family history. Phenotypic features should be taken into account for testing decision. Evaluating the cost-effectiveness of testing all CRC cases <��41 years, as well as how it aligns with the constraints of various healthcare systems, is warranted.

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