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.
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.
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No funding was received for this study.
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Authors and Affiliations
Sorbonne Université, Service de Chirurgie digestive, Hôpital Saint-Antoine, APHP, Paris, France
Antoine Dardenne, Julie Metras, Jeanne Netter & Patrick R. Benusiglio
Paris Cité Université, Service de Gastroentérologie et Oncologie digestive, UF d’Oncogénétique digestive, Hôpital Cochin, APHP, Paris, France
Marion Dhooge & Solenne Farelly
Sorbonne Université, Hôpital Pitié-Salpêtrière, Département de Génétique médicale, APHP, Paris, France
Noémie Basset, Florence Coulet & Patrick R. Benusiglio
Département de Médecine Génomique des Tumeurs et Cancers, Hôpital Cochin, APHP, Université Paris Cité, Paris, France
Albain Chansavang
Service d’Oncologie digestive, Hôpital Européen Georges Pompidou, APHP, Université Paris Cité, Paris, France
Jeanne Netter
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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Antoine Dardenne
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2. Marion Dhooge
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8. Florence Coulet
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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).
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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 (2025). https://doi.org/10.1038/s41431-025-01808-x
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Received:30 August 2024
Revised:22 January 2025
Accepted:03 February 2025
Published:17 March 2025
DOI:https://doi.org/10.1038/s41431-025-01808-x
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