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  • Brief Communication
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Lynch syndrome: influence of additional susceptibility variants on cancer risk


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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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



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).

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