Higher polygenic risk for melanoma is associated with improved survival

Background Although there are well-known prognostic factors for survival from cutaneous melanoma (CM) such as primary tumour thickness and stage of the tumour at diagnosis, the role of germline genetic factors in determining survival is not well understood.\n\nObjective To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS.\n\nMethods We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia (MIA; 5,762 patients with melanoma; 800 deaths from melanoma) and UK Biobank (UKB: 5,220 patients with melanoma; 241 deaths from melanoma). The GWAS were adjusted for age, sex and the first ten genetic principal components, and combined in a fixed-effects inverse-variance-weighted meta-analysis. Significant (P<5×10−8) results were investigated in the Leeds Melanoma Cohort (LMC; 1,947 patients with melanoma; 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts, with replication in the LMC.\n\nResults Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, hazard ratio [HR] 2.09, 95% confidence interval [CI] 1.61-2.71, P=2.08×10−8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR=2.38, 95% CI=1.77—3.21, P=1.07×10−8) on chromosome 7. While neither SNP replicated (P>0.05) in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets and requires confirmation in additional cohorts.\n\nAfter adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR=0.88, 95% CI=0.83—0.94, P=6.93×10−5; I2=88%). The association with the PRS was not replicated (P > 0.05) in LMC, but remained significantly associated with MSS in the meta-analysis of the discovery and replication results.\n\nConclusion We found two loci potentially associated with MSS, and evidence that increased germline genetic susceptibility to develop CM may be associated with improved MSS.\n\n### Competing Interest Statement\n\nJFT has received honoraria for advisory board participation from BMS Australia, MSD Australia, GSK and Provectus Inc, and travel and conference support from GSK, Provectus Inc and Novartis. RAS has received fees for professional services from F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline. The rest of the authors declare no conflict of interest. \n\n### Funding Statement\n\nAcknowledgments and funding QIMR BERGHOFER MEDICAL RESEARCH INSTITUTE 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 UK Biobank (application number 25331), MIA (Australia), QSkin (Australia), Leeds Melanoma Cohort (UK), 23andMe Research (USA) and GWAS summary data from the melanoma meta-analysis consortium. We gratefully acknowledge Simone Cross, as well as Susan List Armitage and the Sample Processing Facility, at QIMR Berghofer Medical Research Institute for their assistance in genotyping MIA samples, and M Teresa Landi at the National Cancer Institute for the genotyping them. We would like to thank the research participants and employees of 23andMe for making this work possible. MELANOMA INSTITUTE AUSTRALIA The authors thank and acknowledge the valuable contributions of Hazel Burke and Valerie Jackrot, and their colleagues, in the clinical, data management, and biospecimen banking teams at Melanoma Institute Australia. This study was supported by funding from Melanoma Institute Australia, the Australian National Health and Medical Research Council (NHMRC) through a program grant to GJM, RAS, JFT & GVL (APP1093017) and from Cancer Institute New South Wales and infrastructure grants from Macquarie University and the Australian Cancer Research Foundation. R.A.S. and G.V.L. are supported by NHMRC Fellowships (APP1141295 for R.A.S), and G.V.L. is supported by the University of Sydney Medical Foundation. LEEDS MELANOMA COHORT The Leeds Melanoma Cohort was funded by the Cancer Research UK (under project grant C8216/A6129 and programme award C588/A19167), and by the National Institutes of Health (NIH) (R01 CA83115) and EU FP6 Network of Excellence award to GenoMEL. Participant recruitment was also supported by the UK National Cancer Research Network. DTB and MMI were supported in part by the Cancer Research UK awards. \n\n### Author Declarations\n\nI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.\n\nYes\n\nThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:\n\nThe Human Research Ethics Committee of QIMR Berghofer Medical Research Institute gave ethical approval for this work.\n\nI 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.\n\nYes\n\nI 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).\n\nYes\n\nI 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.\n\nYes\n\nThe pruning and thresholding (P+T) versions of polygenic risk scores CM can be accessed at the polygenic risk score catalogue (https://www.pgscatalog.org/) upon publication. CM GWAS summary statistics used to generate the LDPred PRSs can be accessed as indicated by Landi et al 2020. Underlying data for the cohorts used in the paper are available through application to the respective cohorts; UKB (http://www.ukbiobank.ac.uk/wp-content/uploads/2012/09/Access-Procedures-2011-1.pdf); MIA (https://www.melanoma.org.au/research/collaborate-on-research-with-mia/); Q-Skin (By application to Q-Skin Principal Investigator David Whiteman David.Whiteman@qimrberghofer.edu.au). \n\n* ABBREVIATIONS\n : \n (AJCC)\n : American Joint Committee on Cancer\n (CM)\n : cutaneous melanoma\n (GWAS)\n : genome-wide association studies\n (HR)\n : hazard ratio\n (ICD)\n : International Classification of Diseases\n (Mb)\n : megabase\n (LD)\n : linkage disequilibrium\n (MIA)\n : Melanoma Institute Australia\n (MSS)\n : melanoma-specific survival\n (MAF)\n : minor allele frequency\n (PRS)\n : polygenic risk score\n (PCs)\n : principal components\n (QSkin)\n : QSkin Sun and Health Study\n (SNP)\n : single nucleotide polymorphism\n (SD)\n : standard deviation\n (UKB)\n : UK Biobank\n (R2)\n : variance\n (LMC)\n : Leeds Melanoma Cohort\n (CI)\n : and Confidence interval