Ability of a polygenic risk score to refine colorectal cancer risk in Lynch syndrome

Background: Polygenic risk scores (PRS) have been used to stratify colorectal cancer (CRC) risk in the general population, whereas its role in Lynch syndrome (LS), the most common type of hereditary CRC, is still conflicting. We aimed to assess the ability of PRS to refine CRC risk prediction in European-descendant LS individuals. Methods: 1,465 LS individuals (557 MLH1, 517 MSH2/EPCAM, 299 MSH6, and 92 PMS2) and 5,656 CRC-free population-based controls from two independent cohorts were included. A 91-Single Nucleotide Polymorphism PRS was applied. A Cox proportional hazard regression model with family as a random effect and a logistic regression analysis, followed by a meta-analysis combining both cohorts were conducted. Results: Overall, we did not observe a statistically significant association between PRS and CRC risk in the entire cohort. Nevertheless, PRS was significantly associated with a slightly increased risk of CRC or advanced adenoma (AA), in those with CRC diagnosed < 50 years, and in individuals with multiple CRCs or AAs diagnosed < 60 years. Conclusion: The PRS may slightly influence CRC risk in LS individuals, in particular in more extreme phenotypes such as early-onset disease. However, the study design and recruitment strategy strongly influence the results of PRS studies. A separate analysis by genes and its combination with other genetic and non-genetic risk factors will help refine its role as a risk modifier in LS. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research has been funded by the Instituto de Salud Carlos III and co-funded by the European Social Fund, ESF investing in your future (grant CM19 00099), the Catalan-Balearic Society of Oncology (2018 grant of the Catalan-Balearic Society of Oncology), the European Union s Horizon 2020 research and innovation program under the EJP RD COFUND-EJP num 825575, the Spanish Ministry of Economy and Competitiveness and the Spanish Ministry of Science and Innovation, cofunded by FEDER funds, a way to build Europe (grants SAF2015 68016 R and PID2019 111254RB I00), CIBERONC (CB16 12 00234) and the Government of Catalonia (SGR 01112). ADV and VM are part of group 55 of CIBERESP. The GSA genotyping was performed at the Spanish National Cancer Research Centre, in the Human Genotyping lab, a member of CeGen, PRB3, and is supported by grant PT17 0019, of the PE I D I 2013-2016, funded by ISCIII and ERDF. ADV was supported by PERIS contract SLT017 20 000042. This research was partially funded by public grants from the Spanish Association Against Cancer (AECC) Scientific Foundation (grant GCTRA18022MORE) and Spanish Ministry for Economy and Competitivity, Instituto de Salud Carlos III, cofunded by FEDER funds, a way to build Europe (FIS PI14 00613). ### 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: Ethics Committee of the Bellvitge University Hospital gave ethical approval for this work 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 All data produced in the present study are available upon reasonable request to the authors