Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations.

<h4>Background</h4>Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors defi...

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Autores principales:	Nicolai Juul Birkbak, Bose Kochupurakkal, Jose M G Izarzugaza, Aron C Eklund, Yang Li, Joyce Liu, Zoltan Szallasi, Ursula A Matulonis, Andrea L Richardson, J Dirk Iglehart, Zhigang C Wang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/af39aee1554b495da94db92c355a9275
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spelling	oai:doaj.org-article:af39aee1554b495da94db92c355a92752021-11-18T08:47:05ZTumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations.1932-620310.1371/journal.pone.0080023https://doaj.org/article/af39aee1554b495da94db92c355a92752013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24265793/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA repair and is associated with treatment outcome in ovarian cancer.<h4>Methods and results</h4>The total number of synonymous and non-synonymous exome mutations (Nmut), and the presence of germline or somatic mutation in BRCA1 or BRCA2 (mBRCA) were extracted from whole-exome sequences of high-grade serous ovarian cancers from The Cancer Genome Atlas (TCGA). Cox regression and Kaplan-Meier methods were used to correlate Nmut with chemotherapy response and outcome. Higher Nmut correlated with a better response to chemotherapy after surgery. In patients with mBRCA-associated cancer, low Nmut was associated with shorter progression-free survival (PFS) and overall survival (OS), independent of other prognostic factors in multivariate analysis. Patients with mBRCA-associated cancers and a high Nmut had remarkably favorable PFS and OS. The association with survival was similar in cancers with either BRCA1 or BRCA2 mutations. In cancers with wild-type BRCA, tumor Nmut was associated with treatment response in patients with no residual disease after surgery.<h4>Conclusions</h4>Tumor Nmut was associated with treatment response and with both PFS and OS in patients with high-grade serous ovarian cancer carrying BRCA1 or BRCA2 mutations. In the TCGA cohort, low Nmut predicted resistance to chemotherapy, and for shorter PFS and OS, while high Nmut forecasts a remarkably favorable outcome in mBRCA-associated ovarian cancer. Our observations suggest that the total mutation burden coupled with BRCA1 or BRCA2 mutations in ovarian cancer is a genomic marker of prognosis and predictor of treatment response. This marker may reflect the degree of deficiency in BRCA-mediated pathways, or the extent of compensation for the deficiency by alternative mechanisms.Nicolai Juul BirkbakBose KochupurakkalJose M G IzarzugazaAron C EklundYang LiJoyce LiuZoltan SzallasiUrsula A MatulonisAndrea L RichardsonJ Dirk IglehartZhigang C WangPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 11, p e80023 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nicolai Juul Birkbak Bose Kochupurakkal Jose M G Izarzugaza Aron C Eklund Yang Li Joyce Liu Zoltan Szallasi Ursula A Matulonis Andrea L Richardson J Dirk Iglehart Zhigang C Wang Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations.
description	<h4>Background</h4>Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA repair and is associated with treatment outcome in ovarian cancer.<h4>Methods and results</h4>The total number of synonymous and non-synonymous exome mutations (Nmut), and the presence of germline or somatic mutation in BRCA1 or BRCA2 (mBRCA) were extracted from whole-exome sequences of high-grade serous ovarian cancers from The Cancer Genome Atlas (TCGA). Cox regression and Kaplan-Meier methods were used to correlate Nmut with chemotherapy response and outcome. Higher Nmut correlated with a better response to chemotherapy after surgery. In patients with mBRCA-associated cancer, low Nmut was associated with shorter progression-free survival (PFS) and overall survival (OS), independent of other prognostic factors in multivariate analysis. Patients with mBRCA-associated cancers and a high Nmut had remarkably favorable PFS and OS. The association with survival was similar in cancers with either BRCA1 or BRCA2 mutations. In cancers with wild-type BRCA, tumor Nmut was associated with treatment response in patients with no residual disease after surgery.<h4>Conclusions</h4>Tumor Nmut was associated with treatment response and with both PFS and OS in patients with high-grade serous ovarian cancer carrying BRCA1 or BRCA2 mutations. In the TCGA cohort, low Nmut predicted resistance to chemotherapy, and for shorter PFS and OS, while high Nmut forecasts a remarkably favorable outcome in mBRCA-associated ovarian cancer. Our observations suggest that the total mutation burden coupled with BRCA1 or BRCA2 mutations in ovarian cancer is a genomic marker of prognosis and predictor of treatment response. This marker may reflect the degree of deficiency in BRCA-mediated pathways, or the extent of compensation for the deficiency by alternative mechanisms.
format	article
author	Nicolai Juul Birkbak Bose Kochupurakkal Jose M G Izarzugaza Aron C Eklund Yang Li Joyce Liu Zoltan Szallasi Ursula A Matulonis Andrea L Richardson J Dirk Iglehart Zhigang C Wang
author_facet	Nicolai Juul Birkbak Bose Kochupurakkal Jose M G Izarzugaza Aron C Eklund Yang Li Joyce Liu Zoltan Szallasi Ursula A Matulonis Andrea L Richardson J Dirk Iglehart Zhigang C Wang
author_sort	Nicolai Juul Birkbak
title	Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations.
title_short	Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations.
title_full	Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations.
title_fullStr	Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations.
title_full_unstemmed	Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations.
title_sort	tumor mutation burden forecasts outcome in ovarian cancer with brca1 or brca2 mutations.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/af39aee1554b495da94db92c355a9275
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Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations.

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