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Lynch syndrome: influence of additional susceptibility variants on cancer risk

European Journal of Human Genetics volume 31, pages 1078–1082 (2023)Cite this article

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Abstract

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.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request, and pending a data transfer agreement between Assistance Publique-Hôpitaux de Paris and the applicant’s institution.

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Acknowledgements

We thank Pr Marie Pierre Buisine for her contribution to the revisions (concerning methylation of MSH2). No funding was received for this study.

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Authors and Affiliations

  1. Département de Génétique médicale et Institut Universitaire de Cancérologie, Hôpital Pitié-Salpêtrière, AP-HP, Sorbonne Université, 47-83 Boulevard de l’Hôpital, F-75013, Paris, France

    Roseline Vibert, Jasmine Hasnaoui, Alexandre Perrier, Noémie Basset, Camille Desseignes, Martine Muleris, Romain Nicolle, Florence Coulet & Patrick R. Benusiglio

  2. Laboratoire de Probabilités, Statistique et Modélisation, CNRS UMR 8001, Sorbonne Université, Paris, France

    Alexandra Lefebvre

  3. Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 et SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, 184 rue du Faubourg Saint-Antoine, F-75012, Paris, France

    Alexandra Lefebvre, Alex Duval, Martine Muleris, Florence Coulet & Patrick R. Benusiglio

  4. Département de Génétique, Institut Curie, Paris, France

    Chrystelle Colas & Mathilde Warcoin

  5. INSERM U830, Université Paris Cité, Paris, France

    Chrystelle Colas

  6. Service de Gastroentérologie et Oncologie digestive, Hôpital Cochin, AP-HP Centre, Paris, France

    Marion Dhooge & Solenne Farelly

  7. Fédération de Génétique et Médecine Génomique, Hôpital Cochin, AP-HP, Centre-Université Paris Cité, Paris, France

    Albain Chansavang & Nadim Hamzaoui

  8. Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France

    Albain Chansavang & Nadim Hamzaoui

  9. Institut du Cancer Paris CARPEM, APHP, Département de Médecine Génomique des tumeurs et cancers, APHP, Centre - Université Paris Cité, Paris, France

    Pierre Laurent-Puig, Diane Moliere, Jeanne Netter & Géraldine Perkins

  10. Service de Chirurgie Générale et Digestive, Hôpital Saint-Antoine AP-HP, Sorbonne Université, 184, rue du Faubourg Saint-Antoine, 75012, Paris, France

    Julie Metras & Patrick R. Benusiglio

  11. Service de Neurologie 2 Mazarin, Hôpital Pitié-Salpêtrière, AP-HP, Sorbonne Université, 47-83 Boulevard de l’Hôpital, F-75013, Paris, France

    Mehdi Touat

  12. Sorbonne Université, Institut du Cerveau—Paris Brain Institute - ICM, Inserm, CNRS, SIRIC CURAMUS, Onconeurothèque, AP-HP 47-83 Boulevard de l’Hôpital, F-75013, Paris, France

    Mehdi Touat

  13. Département de Neuropathologie Raymond Escourolle, Hôpital Pitié-Salpêtrière, AP-HP, Sorbonne Université, 47-83 Boulevard de l’Hôpital, F-75013, Paris, France

    Franck Bielle

  14. Sorbonne-Université, équipe BMX—UMS PASS—91 Bd de l’hôpital, F-75013, Paris, France

    Karim Labreche

Authors
  1. Roseline Vibert
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  2. Jasmine Hasnaoui
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  3. Alexandre Perrier
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  4. Alexandra Lefebvre
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  5. Chrystelle Colas
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  6. Marion Dhooge
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  7. Noémie Basset
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  8. Albain Chansavang
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  9. Camille Desseignes
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  10. Alex Duval
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  11. Solenne Farelly
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  12. Nadim Hamzaoui
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  13. Pierre Laurent-Puig
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  14. Julie Metras
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  15. Diane Moliere
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  16. Martine Muleris
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  17. Jeanne Netter
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  18. Mehdi Touat
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  19. Franck Bielle
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  20. Karim Labreche
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  21. Romain Nicolle
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  22. Géraldine Perkins
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  23. Mathilde Warcoin
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  24. Florence Coulet
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  25. Patrick R. Benusiglio
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Contributions

RV, PRB: designed the study, acquired and analyzed data, and wrote the manuscript. JH: data management, research governance. AP, FB, MT: complementary data collection and analysis. AL: statistical analyses. AD, FC: contribution to study design. CC, MD, SF, PLP, JM, DM,JN, GP: genetic counseling, patient care. NB, AC, CD, NH, MM, RN, AP, FC: germline sequencing and interpretation. All authors approved the final version, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Roseline Vibert.

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Competing interests

PRB has received honoraria from AstraZeneca, MSD and BMS. The other authors declare no competing interests.

Ethical approval

The study was approved by the ethics evaluation committee of Inserm, the Institutional Review Board (IRB00003888, IORG0003254, FWA00005831) of the French Institute of medical research and Health (Opinion number 22-878).

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Vibert, R., Hasnaoui, J., Perrier, A. et al. Lynch syndrome: influence of additional susceptibility variants on cancer risk. Eur J Hum Genet 31, 1078–1082 (2023). https://doi.org/10.1038/s41431-023-01367-z

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