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A genome-wide association study of germline variation and melanoma prognosis

BACKGROUND: The high mortality of cutaneous melanoma (CM) is partly due to unpredictable patterns of disease progression in patients with early-stage lesions. The reliable prediction of advanced disease risk from early-stage CM, is an urgent clinical need, especially given the recent expansion of im...

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Autores principales: Chat, Vylyny, Dagayev, Sasha, Moran, Una, Snuderl, Matija, Weber, Jeffrey, Ferguson, Robert, Osman, Iman, Kirchhoff, Tomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894711/
https://www.ncbi.nlm.nih.gov/pubmed/36741706
http://dx.doi.org/10.3389/fonc.2022.1050741
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author Chat, Vylyny
Dagayev, Sasha
Moran, Una
Snuderl, Matija
Weber, Jeffrey
Ferguson, Robert
Osman, Iman
Kirchhoff, Tomas
author_facet Chat, Vylyny
Dagayev, Sasha
Moran, Una
Snuderl, Matija
Weber, Jeffrey
Ferguson, Robert
Osman, Iman
Kirchhoff, Tomas
author_sort Chat, Vylyny
collection PubMed
description BACKGROUND: The high mortality of cutaneous melanoma (CM) is partly due to unpredictable patterns of disease progression in patients with early-stage lesions. The reliable prediction of advanced disease risk from early-stage CM, is an urgent clinical need, especially given the recent expansion of immune checkpoint inhibitor therapy to the adjuvant setting. In our study, we comprehensively investigated the role of germline variants as CM prognostic markers. METHODS: We performed a genome-wide association analysis in two independent cohorts of N=551 (discovery), and N=550 (validation) early-stage immunotherapy-naïve melanoma patients. A multivariable Cox proportional hazard regression model was used to identify associations with overall survival in the discovery group, followed by a validation analysis. Transcriptomic profiling and survival analysis were used to elucidate the biological relevance of candidate genes associated with CM progression. RESULTS: We found two independent associations of germline variants with melanoma prognosis. The alternate alleles of these two SNPs were both associated with an increased risk of death [rs60970102 in MELK: HR=3.14 (2.05–4.81), p=1.48×10(-7); and rs77480547 in SH3BP4: HR=3.02 (2.02–4.52), p=7.58×10(-8), both in the pooled cohort]. The addition of the combined risk alleles (CRA) of the identified variants into the prognostic model improved the predictive power, as opposed to a model of clinical covariates alone. CONCLUSIONS: Our study provides suggestive evidence of novel melanoma germline prognostic markers, implicating two candidate genes: an oncogene MELK and a tumor suppressor SH3BP4, both previously suggested to affect CM progression. Pending further validation, these findings suggest that the genetic factors may improve the prognostic stratification of high-risk early-stage CM patients, and propose putative biological insights for potential therapeutic investigation of these targets to prevent aggressive outcome from early-stage melanoma.
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spelling pubmed-98947112023-02-03 A genome-wide association study of germline variation and melanoma prognosis Chat, Vylyny Dagayev, Sasha Moran, Una Snuderl, Matija Weber, Jeffrey Ferguson, Robert Osman, Iman Kirchhoff, Tomas Front Oncol Oncology BACKGROUND: The high mortality of cutaneous melanoma (CM) is partly due to unpredictable patterns of disease progression in patients with early-stage lesions. The reliable prediction of advanced disease risk from early-stage CM, is an urgent clinical need, especially given the recent expansion of immune checkpoint inhibitor therapy to the adjuvant setting. In our study, we comprehensively investigated the role of germline variants as CM prognostic markers. METHODS: We performed a genome-wide association analysis in two independent cohorts of N=551 (discovery), and N=550 (validation) early-stage immunotherapy-naïve melanoma patients. A multivariable Cox proportional hazard regression model was used to identify associations with overall survival in the discovery group, followed by a validation analysis. Transcriptomic profiling and survival analysis were used to elucidate the biological relevance of candidate genes associated with CM progression. RESULTS: We found two independent associations of germline variants with melanoma prognosis. The alternate alleles of these two SNPs were both associated with an increased risk of death [rs60970102 in MELK: HR=3.14 (2.05–4.81), p=1.48×10(-7); and rs77480547 in SH3BP4: HR=3.02 (2.02–4.52), p=7.58×10(-8), both in the pooled cohort]. The addition of the combined risk alleles (CRA) of the identified variants into the prognostic model improved the predictive power, as opposed to a model of clinical covariates alone. CONCLUSIONS: Our study provides suggestive evidence of novel melanoma germline prognostic markers, implicating two candidate genes: an oncogene MELK and a tumor suppressor SH3BP4, both previously suggested to affect CM progression. Pending further validation, these findings suggest that the genetic factors may improve the prognostic stratification of high-risk early-stage CM patients, and propose putative biological insights for potential therapeutic investigation of these targets to prevent aggressive outcome from early-stage melanoma. Frontiers Media S.A. 2023-01-19 /pmc/articles/PMC9894711/ /pubmed/36741706 http://dx.doi.org/10.3389/fonc.2022.1050741 Text en Copyright © 2023 Chat, Dagayev, Moran, Snuderl, Weber, Ferguson, Osman and Kirchhoff https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Chat, Vylyny
Dagayev, Sasha
Moran, Una
Snuderl, Matija
Weber, Jeffrey
Ferguson, Robert
Osman, Iman
Kirchhoff, Tomas
A genome-wide association study of germline variation and melanoma prognosis
title A genome-wide association study of germline variation and melanoma prognosis
title_full A genome-wide association study of germline variation and melanoma prognosis
title_fullStr A genome-wide association study of germline variation and melanoma prognosis
title_full_unstemmed A genome-wide association study of germline variation and melanoma prognosis
title_short A genome-wide association study of germline variation and melanoma prognosis
title_sort genome-wide association study of germline variation and melanoma prognosis
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894711/
https://www.ncbi.nlm.nih.gov/pubmed/36741706
http://dx.doi.org/10.3389/fonc.2022.1050741
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