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Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients

Patients with late stage resected cutaneous melanoma have poor overall survival (OS) and experience irreversible adverse events from systemic therapy. There is a clinical need to identify biomarkers to predict outcome. Performing germline/tumour whole-exome sequencing of 44 stage III/IV melanoma pat...

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Autores principales: Aoude, Lauren G., Bonazzi, Vanessa F., Brosda, Sandra, Patel, Kalpana, Koufariotis, Lambros T., Oey, Harald, Nones, Katia, Wood, Scott, Pearson, John V., Lonie, James M., Arneil, Melissa, Atkinson, Victoria, Smithers, B. Mark, Waddell, Nicola, Barbour, Andrew P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572377/
https://www.ncbi.nlm.nih.gov/pubmed/33077847
http://dx.doi.org/10.1038/s41598-020-74956-3
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author Aoude, Lauren G.
Bonazzi, Vanessa F.
Brosda, Sandra
Patel, Kalpana
Koufariotis, Lambros T.
Oey, Harald
Nones, Katia
Wood, Scott
Pearson, John V.
Lonie, James M.
Arneil, Melissa
Atkinson, Victoria
Smithers, B. Mark
Waddell, Nicola
Barbour, Andrew P.
author_facet Aoude, Lauren G.
Bonazzi, Vanessa F.
Brosda, Sandra
Patel, Kalpana
Koufariotis, Lambros T.
Oey, Harald
Nones, Katia
Wood, Scott
Pearson, John V.
Lonie, James M.
Arneil, Melissa
Atkinson, Victoria
Smithers, B. Mark
Waddell, Nicola
Barbour, Andrew P.
author_sort Aoude, Lauren G.
collection PubMed
description Patients with late stage resected cutaneous melanoma have poor overall survival (OS) and experience irreversible adverse events from systemic therapy. There is a clinical need to identify biomarkers to predict outcome. Performing germline/tumour whole-exome sequencing of 44 stage III/IV melanoma patients we identified pathogenic germline mutations in CDKN2A, CDK4, ATM, POLH, MRE11A, RECQL4 and XPC, affecting 7/44 patients. These mutations were associated with poor OS (p = 0.0082). We confirmed our findings in The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma cohort where we identified pathogenic variants in 40/455 patients (p = 0.0203). Combining these cohorts (n = 499) further strengthened these findings showing germline carriers had worse OS (p = 0.0009). Additionally, we determined whether tumour mutation burden (TMB) or BRAF status were prognostic markers of survival. Low TMB rate (< 20 Mut/Mb; p = 0.0034) and BRAF p.V600 mutation (p = 0.0355) were associated with worse progression-free survival. Combining these biomarkers indicated that V600 mutant patients had significantly lower TMB (p = 0.0155). This was confirmed in the TCGA (n = 443, p = 0.0007). Integrative analysis showed germline mutation status conferred the highest risk (HR 5.2, 95% CI 1.72–15.7). Stage IV (HR 2.5, 0.74–8.6) and low TMB (HR 2.3, 0.57–9.4) were similar, whereas BRAF V600 status was the weakest prognostic biomarker (HR 1.5, 95% CI 0.44–5.2).
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spelling pubmed-75723772020-10-21 Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients Aoude, Lauren G. Bonazzi, Vanessa F. Brosda, Sandra Patel, Kalpana Koufariotis, Lambros T. Oey, Harald Nones, Katia Wood, Scott Pearson, John V. Lonie, James M. Arneil, Melissa Atkinson, Victoria Smithers, B. Mark Waddell, Nicola Barbour, Andrew P. Sci Rep Article Patients with late stage resected cutaneous melanoma have poor overall survival (OS) and experience irreversible adverse events from systemic therapy. There is a clinical need to identify biomarkers to predict outcome. Performing germline/tumour whole-exome sequencing of 44 stage III/IV melanoma patients we identified pathogenic germline mutations in CDKN2A, CDK4, ATM, POLH, MRE11A, RECQL4 and XPC, affecting 7/44 patients. These mutations were associated with poor OS (p = 0.0082). We confirmed our findings in The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma cohort where we identified pathogenic variants in 40/455 patients (p = 0.0203). Combining these cohorts (n = 499) further strengthened these findings showing germline carriers had worse OS (p = 0.0009). Additionally, we determined whether tumour mutation burden (TMB) or BRAF status were prognostic markers of survival. Low TMB rate (< 20 Mut/Mb; p = 0.0034) and BRAF p.V600 mutation (p = 0.0355) were associated with worse progression-free survival. Combining these biomarkers indicated that V600 mutant patients had significantly lower TMB (p = 0.0155). This was confirmed in the TCGA (n = 443, p = 0.0007). Integrative analysis showed germline mutation status conferred the highest risk (HR 5.2, 95% CI 1.72–15.7). Stage IV (HR 2.5, 0.74–8.6) and low TMB (HR 2.3, 0.57–9.4) were similar, whereas BRAF V600 status was the weakest prognostic biomarker (HR 1.5, 95% CI 0.44–5.2). Nature Publishing Group UK 2020-10-19 /pmc/articles/PMC7572377/ /pubmed/33077847 http://dx.doi.org/10.1038/s41598-020-74956-3 Text en © The Author(s) 2020 Open Access This 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/.
spellingShingle Article
Aoude, Lauren G.
Bonazzi, Vanessa F.
Brosda, Sandra
Patel, Kalpana
Koufariotis, Lambros T.
Oey, Harald
Nones, Katia
Wood, Scott
Pearson, John V.
Lonie, James M.
Arneil, Melissa
Atkinson, Victoria
Smithers, B. Mark
Waddell, Nicola
Barbour, Andrew P.
Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients
title Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients
title_full Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients
title_fullStr Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients
title_full_unstemmed Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients
title_short Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients
title_sort pathogenic germline variants are associated with poor survival in stage iii/iv melanoma patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572377/
https://www.ncbi.nlm.nih.gov/pubmed/33077847
http://dx.doi.org/10.1038/s41598-020-74956-3
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