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

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

doi:10.1186/s12967-022-03613-2

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

J Transl Med. 2022 Sep 5;20(1):403. doi: 10.1186/s12967-022-03613-2.

Authors

Mathias Seviiri^{1

2

3}, Richard A Scolyer^{4

5

6

7}, D Timothy Bishop⁸, Julia A Newton-Bishop⁸, Mark M Iles^{9

10}, Serigne N Lo^{4

5}, Johnathan R Stretch^{4

5

11}, Robyn P M Saw^{4

5

11}, Omgo E Nieweg^{4

5

11}, Kerwin F Shannon^{4

11

12}, Andrew J Spillane^{4

5

13}, Scott D Gordon¹⁴, Catherine M Olsen^{15

16}, David C Whiteman¹⁵, Maria Teresa Landi¹⁷, John F Thompson^{4

5

11}, Georgina V Long^{4

5

18

19}, Stuart MacGregor^{20

21}, Matthew H Law^{22

23}

Affiliations

¹ Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia. Mathias.Seviiri@qimrberghofer.edu.au.
² School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia. Mathias.Seviiri@qimrberghofer.edu.au.
³ Center for Genomics and Personalised Health, Queensland University of Technology, Brisbane, QLD, Australia. Mathias.Seviiri@qimrberghofer.edu.au.
⁴ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.
⁵ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁶ Department of Tissue Oncology and Diagnostic Pathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
⁷ NSW Health Pathology, Sydney, NSW, Australia.
⁸ Division of Haematology and Immunology, Leeds Institute of Medical Research at St James', University of Leeds, Leeds, UK.
⁹ St James's Institute of Medical Research, University of Leeds, Leeds, UK.
¹⁰ Leeds Institute of Data Analytics, University of Leeds, Leeds, UK.
¹¹ Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
¹² Sydney Head & Neck Cancer Institute, Chris O'Brien Lifehouse Cancer Center, Sydney, NSW, Australia.
¹³ Department of Breast and Melanoma Surgery, Royal North Shore Hospital, Sydney, NSW, Australia.
¹⁴ Genetic Epidemiology Lab, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹⁵ Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹⁶ Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
¹⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁸ Department of Medical Oncology, Mater Hospital, North Sydney, NSW, Australia.
¹⁹ Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia.
²⁰ Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia.
²¹ School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
²² Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia. matthew.law@qimrberghofer.edu.au.
²³ School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia. matthew.law@qimrberghofer.edu.au.

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.

Keywords: Genome-wide association study; Melanoma; Melanoma-specific survival; Polygenic risk score; Skin cancer.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Melanoma* / genetics
Melanoma, Cutaneous Malignant
Polymorphism, Single Nucleotide / genetics
Skin Neoplasms* / genetics
Ultraviolet Rays

Abstract

Publication types

MeSH terms

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