Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting
Year: 2022
Type: article
Study design: Observational Study
Abstract: BACKGROUND: The role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood. OBJECTIVE: 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. METHODS: We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA; 5,762 patients with melanoma; 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma; 241 melanoma deaths), and combined them in a fixed-effects 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. RESULTS: Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, HR = 2.09, 95%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 in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets. After 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%). However, this was only driven by the high UV setting cohort (MIA HR = 0.84, 95% CI = 0.78-0.90). CONCLUSION: We found two loci potentially associated with MSS. Increased genetic susceptibility to develop CM is associated with improved MSS in a high UV setting.
Authors: Mathias Seviiri, Richard A. Scolyer, D. Timothy Bishop, Julia A. Newton-Bishop, Mark M. Iles, Serigne N. Lo, Johnathan R. Stretch, Robyn P. M. Saw, Omgo E. Nieweg, Kerwin F. Shannon, Andrew J. Spillane, Scott D. Gordon, Catherine M. Olsen, David C. Whiteman, Maria Teresa Landi, John F. Thompson, Georgina V. Long, Stuart MacGregor, Matthew H. Law
Institutions: Queensland University of Technology, QIMR Berghofer Medical Research Institute, The University of Sydney, Royal Prince Alfred Hospital, Melanoma Institute Australia, NSW Health Pathology, University of Leeds, Chris O’Brien Lifehouse, Royal North Shore Hospital, The University of Queensland, National Institutes of Health, Division of Cancer Epidemiology and Genetics
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,190
Funders: QIMR Berghofer Medical Research Institute, NSW Health Pathology, Cancer Research UK, University of Leeds, University of Sydney, Queensland University of Technology, Melanoma Institute Australia, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, Faculty of Medicine and Health, University of Sydney, National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Cancer Institute
Awards: G1057596923, QSKIN: the genetics of skin cancer, Improving clinical outcomes of melanoma patients, Molecular determinants of risk, progression and treatment response in melanoma, G5617545779, G5850737185, Genetic Epidemiology of Melanoma (GenoMel), Generating the evidence to control cancer and optimise outcomes, G7956840597
OpenAlex ID: W4294653791