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

European Journal of Human Genetics volume 33, pages 810–813 (2025)Cite this article

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Abstract

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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Fig. 1: Study flowchart with pathogenic germline variant detection rates.
Fig. 2: Pathogenic germline variants identified in all cases, and according to group.

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Data availability

Data are available on reasonable request from European Union researchers, and pending a data transfer agreement between institutions.

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Acknowledgements

We thank our collaborators for referring their patients to Clinical Cancer Genetics, and for their contribution to patient management, among them Pr. Yann Parc, Pr. Magali Svrcek, Pr. Jérémie Lefèbvre, Pr. Thierry André, Dr. Romain Cohen, Dr. Thomas Pudlarz, Dr. Anna Pellat, Pr. Stanislas Chaussade, Dr. Arthur Belle, Pr. Romain Coriat, Pr. Max Barret, Dr. Catherine Brezault and Dr Mahaut Leconte.

Funding

No funding was received for this study.

Author information

Authors and Affiliations

  1. Sorbonne Université, Service de Chirurgie digestive, Hôpital Saint-Antoine, APHP, Paris, France

    Antoine Dardenne, Julie Metras, Jeanne Netter & Patrick R. Benusiglio

  2. Paris Cité Université, Service de Gastroentérologie et Oncologie digestive, UF d’Oncogénétique digestive, Hôpital Cochin, APHP, Paris, France

    Marion Dhooge & Solenne Farelly

  3. Sorbonne Université, Hôpital Pitié-Salpêtrière, Département de Génétique médicale, APHP, Paris, France

    Noémie Basset, Florence Coulet & Patrick R. Benusiglio

  4. Département de Médecine Génomique des Tumeurs et Cancers, Hôpital Cochin, APHP, Université Paris Cité, Paris, France

    Albain Chansavang

  5. Service d’Oncologie digestive, Hôpital Européen Georges Pompidou, APHP, Université Paris Cité, Paris, France

    Jeanne Netter

  6. Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 et SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Paris, France

    Florence Coulet & Patrick R. Benusiglio

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  1. Antoine Dardenne
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  2. Marion Dhooge
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Contributions

Genetic counseling, patient management: A.D., M.D., J.M., S.F., J.N., P.R.B. Data collection and interpretation: A.D., M.D., J.M., S.F., P.R.B. Genetic analyses: N.B., A.C., F.C. Manuscript writing: P.R.B. Final approval of manuscript: all authors.

Corresponding author

Correspondence to Patrick R. Benusiglio.

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Competing interests

P.R.B. has received honoraria from AstraZeneca, M.S.D. and B.M.S., and funding support from Astrazeneca (unrelated to the present study).

Ethical approval

In France, ethics committee approval is not required for retrospective studies such as this one. However, and in accordance with French law, all participants were sent an information note with the possibility to opt out.

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Dardenne, A., Dhooge, M., Basset, N. et al. Pathogenic germline variants in patients with early-onset colorectal cancer according to phenotype. Eur J Hum Genet 33, 810–813 (2025). https://doi.org/10.1038/s41431-025-01808-x

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