Cargando…
Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting
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...
Autores principales: | , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9446843/ https://www.ncbi.nlm.nih.gov/pubmed/36064556 http://dx.doi.org/10.1186/s12967-022-03613-2 |
_version_ | 1784783729503240192 |
---|---|
author | Seviiri, Mathias Scolyer, Richard A. Bishop, D. Timothy Newton-Bishop, Julia A. Iles, Mark M. Lo, Serigne N. Stretch, Johnathan R. Saw, Robyn P. M. Nieweg, Omgo E. Shannon, Kerwin F. Spillane, Andrew J. Gordon, Scott D. Olsen, Catherine M. Whiteman, David C. Landi, Maria Teresa Thompson, John F. Long, Georgina V. MacGregor, Stuart Law, Matthew H. |
author_facet | Seviiri, Mathias Scolyer, Richard A. Bishop, D. Timothy Newton-Bishop, Julia A. Iles, Mark M. Lo, Serigne N. Stretch, Johnathan R. Saw, Robyn P. M. Nieweg, Omgo E. Shannon, Kerwin F. Spillane, Andrew J. Gordon, Scott D. Olsen, Catherine M. Whiteman, David C. Landi, Maria Teresa Thompson, John F. Long, Georgina V. MacGregor, Stuart Law, Matthew H. |
author_sort | Seviiri, Mathias |
collection | PubMed |
description | 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03613-2. |
format | Online Article Text |
id | pubmed-9446843 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-94468432022-09-07 Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting Seviiri, Mathias Scolyer, Richard A. Bishop, D. Timothy Newton-Bishop, Julia A. Iles, Mark M. Lo, Serigne N. Stretch, Johnathan R. Saw, Robyn P. M. Nieweg, Omgo E. Shannon, Kerwin F. Spillane, Andrew J. Gordon, Scott D. Olsen, Catherine M. Whiteman, David C. Landi, Maria Teresa Thompson, John F. Long, Georgina V. MacGregor, Stuart Law, Matthew H. J Transl Med Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03613-2. BioMed Central 2022-09-05 /pmc/articles/PMC9446843/ /pubmed/36064556 http://dx.doi.org/10.1186/s12967-022-03613-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Seviiri, Mathias Scolyer, Richard A. Bishop, D. Timothy Newton-Bishop, Julia A. Iles, Mark M. Lo, Serigne N. Stretch, Johnathan R. Saw, Robyn P. M. Nieweg, Omgo E. Shannon, Kerwin F. Spillane, Andrew J. Gordon, Scott D. Olsen, Catherine M. Whiteman, David C. Landi, Maria Teresa Thompson, John F. Long, Georgina V. MacGregor, Stuart Law, Matthew H. Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting |
title | Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting |
title_full | Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting |
title_fullStr | Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting |
title_full_unstemmed | Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting |
title_short | Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting |
title_sort | higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9446843/ https://www.ncbi.nlm.nih.gov/pubmed/36064556 http://dx.doi.org/10.1186/s12967-022-03613-2 |
work_keys_str_mv | AT seviirimathias higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT scolyerricharda higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT bishopdtimothy higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT newtonbishopjuliaa higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT ilesmarkm higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT loserignen higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT stretchjohnathanr higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT sawrobynpm higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT niewegomgoe higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT shannonkerwinf higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT spillaneandrewj higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT gordonscottd higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT olsencatherinem higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT whitemandavidc higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT landimariateresa higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT thompsonjohnf higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT longgeorginav higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT macgregorstuart higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting AT lawmatthewh higherpolygenicriskformelanomaisassociatedwithimprovedsurvivalinahighultravioletradiationsetting |