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Open Access 01-12-2022 | Nevi | Research

Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation 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

Published in: Journal of Translational Medicine | Issue 1/2022

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.

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Title: Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation 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
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Nevi
Melanoma
Melanoma
Published in: Journal of Translational Medicine / Issue 1/2022
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-022-03613-2

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