Re-weighting MC1R, ASIP and IRF4 risk variants optimises polygenic risk scores for keratinocyte cancer stratification in solid organ transplant recipients

Introduction Solid organ transplant recipients (SOTRs) are at much higher risk of developing squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), compared to the general population. Previous studies have derived genetics-based predictors (polygenic risk scores, PRS) of SCC and BCC risk in SOTRs by assuming that genetic risk variants act in the same way in the general population as in SOTRs, but this assumption has not been fully tested. Objective To investigate whether known genetic risk variants for SCC and BCC have different effect sizes in SOTRs versus in non-transplantees, and if a re-weighted PRS would improve risk prediction. Methods We conducted genome-wide association studies for SCC and BCC separately in the non-transplant general population and in SOTRs, and compared the risks associated with selected common genetic variants for KC risk in SOTR vs non-transplant individuals from the UK Biobank. For regions with an increased log odds ratio in SOTRs, PRSs including these weights were validated in the QSkin study, and applied to the Australian STAR SOTR cohort. Results Effect sizes for functional variants in MC1R (rs1805007), ASIP (rs6059655), and IRF4 (rs12203592) were much more strongly associated with the risk of KC in SOTRs than in non-transplantees. The proportional increase in the effect sizes ranged from 1.9-fold for rs6059655 and BCC risk (SOTRs log (OR)=0.49, 95%CI=0.00-0.98 vs log (OR)=0.26, 95%CI=0.24-0.30 in non-transplantees) to as high as 4.8-fold for rs1805007 and SCC risk (SOTR log (OR)=0.88, 95% CI=0.41-1.35 vs log (OR)=0.18, 95% CI=0.12-0.24 in non-transplantees). PRS with SOTR derived weights for these SNPs showed improved SCC/BCC risk stratification in the STAR Cohort, with the optimised PRS reclassifying 19% of SCC cases vs 8% using the standard PRS, and 18% of BCC cases vs 12% using the standard PRS. Conclusion Effect sizes for SCC and BCC risk for genetic variants in the MC1R, ASIP and IRF4 genes are elevated in SOTRs, and correctly weighting these variants improves risk stratification based on polygenic risk. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study was supported by a program grant (APP1073898) and a project grant (APP1063061) from the Australian National Health and Medical Research Council (NHMRC). SM and DCW are supported by Research Fellowships from the NHMRC. MS was supported by the Australian Government Research Training Program (RTP) and the Faculty of Health Scholarship at Queensland University of Technology, Australia. This study was conducted using data from the UK Biobank (application number 25331), and the QSkin Sun and Health Study (Australia), and the STAR Cohort (Australia). ### 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: The Human Research Ethics Committee of QIMR Berghofer Medical Research Institute gave ethical approval to this work, as well as the ethical approval for the QSkin Sun and Health Study (QSkin). The human research ethics committees at the Metro South Hospital and Health Service, Brisbane, Australia and at QIMR Berghofer Medical Research Institute, Brisbane provided ethical oversight to the The Skin Tumours in Allograft Recipients (STAR) Cohort study, while The National North West Multi-Centre Research Ethics Committee in the United Kingdom provided the ethical oversight over the United Kingdom Biobank. All participants provided written informed consent. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The polygenic scores generated in this study will be accessed through the Polygenic Score Catalog (). The underlying data for each cohort can be accessed through application to the UK Biobank (), QSkin (Principal Investigator David Whiteman at David.Whiteman{at}qimrberghofer.edu.au), and STAR (Principal Investigator Adele Green at Adele.Green{at}qimrberghofer.edu.au).