Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank

Background: Lynch syndrome (LS) is an inherited cancer predisposition syndrome caused by genetic variants affecting DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. Cancer risk in LS is estimated from cohorts of individuals ascertained by family history of cancer, which is known to upwardly bias estimates. Methods: The InSiGHT Database classifies MMR gene variants by pathogenicity through expert panel review of published evidence. 830 carriers of pathogenic or likely pathogenic (pathMMR) MMR gene variants from InSiGHT were identified in 454,756 UK Biobank participants using whole exome sequence. Nelson-Aalen survival analysis was used to estimate cumulative incidence of colorectal, endometrial, and breast cancer. Results: Cumulative incidence of colorectal and endometrial cancer by age 70 was elevated in pathMMR carriers compared to non-carriers (colorectal: 11.8% (95% CI: 9.5 - 14.6) vs. 1.7% (1.6 - 1.7), endometrial: 13.4% (10.2 - 17.6) vs. 1.0% (0.9 - 1.0)), but the magnitude of this increase differed between genes. Cumulative breast cancer incidence by age 70 was not elevated in pathMMR carriers compared to non-carriers (8.9% (6.3 - 12.4) vs. 7.5% (7.4 - 7.6)). Cumulative cancer incidence estimates in UK Biobank were similar to estimates from the Prospective Lynch Syndrome Database for all genes and cancers, except there was no evidence for elevated endometrial cancer risk in carriers of pathogenic PMS2 variants in UK Biobank. Conclusion: These results can be used to inform the management of incidentally identified cases of LS. For example, they support the application of existing colorectal cancer surveillance strategies for LS in incidentally identified cases. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement EF was supported by the UKRI's Biotechnology and Biological Sciences Research Council (BBSRC, BB/S508032/1). PN was supported by UKRI's Medical Research Council (MC\_PC\_U127592696 MC\_PC\_U127561128 and MC\_UU\_00007/10) and the BBSRC (BBS/E/RL/230001A). AT acknowledges funding from the BBSRC through programme grants BBS/E/D/10002070 and BBS/E/D/30002275, MRC research grant MR/P015514/1, and HDR-UK award HDR-9004. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data used was obtained from UK Biobank under application 44986. National Research Ethics Service Committee North West-Haydock gave ethical approval for the UK Biobank project (REC reference: 21/NW/0157). An electronic signed consent was obtained from all UK Biobank participants. More information can be found at https://biobank.ctsu.ox.ac.uk/crystal/crystal/docs/Consent.pdf I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data can be obtained through application to UK Biobank.