Discovery analysis of TCGA data reveals association between germline genotype and survival in ovarian cancer patients.

<h4>Background</h4>Ovarian cancer remains a significant public health burden, with the highest mortality rate of all the gynecological cancers. This is attributable to the late stage at which the majority of ovarian cancers are diagnosed, coupled with the low and variable response of adv...

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Autores principales:	Rosemary Braun, Richard Finney, Chunhua Yan, Qing-Rong Chen, Ying Hu, Michael Edmonson, Daoud Meerzaman, Kenneth Buetow
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/906954cf1fef46d280fd7e95b730f7cd
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spelling	oai:doaj.org-article:906954cf1fef46d280fd7e95b730f7cd2021-11-18T07:52:32ZDiscovery analysis of TCGA data reveals association between germline genotype and survival in ovarian cancer patients.1932-620310.1371/journal.pone.0055037https://doaj.org/article/906954cf1fef46d280fd7e95b730f7cd2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23555554/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Ovarian cancer remains a significant public health burden, with the highest mortality rate of all the gynecological cancers. This is attributable to the late stage at which the majority of ovarian cancers are diagnosed, coupled with the low and variable response of advanced tumors to standard chemotherapies. To date, clinically useful predictors of treatment response remain lacking. Identifying the genetic determinants of ovarian cancer survival and treatment response is crucial to the development of prognostic biomarkers and personalized therapies that may improve outcomes for the late-stage patients who comprise the majority of cases.<h4>Methods</h4>To identify constitutional genetic variations contributing to ovarian cancer mortality, we systematically investigated associations between germline polymorphisms and ovarian cancer survival using data from The Cancer Genome Atlas Project (TCGA). Using stage-stratified Cox proportional hazards regression, we examined >650,000 SNP loci for association with survival. We additionally examined whether the association of significant SNPs with survival was modified by somatic alterations.<h4>Results</h4>Germline polymorphisms at rs4934282 (AGAP11/C10orf116) and rs1857623 (DNAH14) were associated with stage-adjusted survival (p= 1.12e-07 and 1.80e-07, FDR q= 1.2e-04 and 2.4e-04, respectively). A third SNP, rs4869 (C10orf116), was additionally identified as significant in the exome sequencing data; it is in near-perfect LD with rs4934282. The associations with survival remained significant when somatic alterations.<h4>Conclusions</h4>Discovery analysis of TCGA data reveals germline genetic variations that may play a role in ovarian cancer survival even among late-stage cases. The significant loci are located near genes previously reported as having a possible relationship to platinum and taxol response. Because the variant alleles at the significant loci are common (frequencies for rs4934282 A/C alleles = 0.54/0.46, respectively; rs1857623 A/G alleles = 0.55/0.45, respectively) and germline variants can be assayed noninvasively, our findings provide potential targets for further exploration as prognostic biomarkers and individualized therapies.Rosemary BraunRichard FinneyChunhua YanQing-Rong ChenYing HuMichael EdmonsonDaoud MeerzamanKenneth BuetowPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 3, p e55037 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rosemary Braun Richard Finney Chunhua Yan Qing-Rong Chen Ying Hu Michael Edmonson Daoud Meerzaman Kenneth Buetow Discovery analysis of TCGA data reveals association between germline genotype and survival in ovarian cancer patients.
description	<h4>Background</h4>Ovarian cancer remains a significant public health burden, with the highest mortality rate of all the gynecological cancers. This is attributable to the late stage at which the majority of ovarian cancers are diagnosed, coupled with the low and variable response of advanced tumors to standard chemotherapies. To date, clinically useful predictors of treatment response remain lacking. Identifying the genetic determinants of ovarian cancer survival and treatment response is crucial to the development of prognostic biomarkers and personalized therapies that may improve outcomes for the late-stage patients who comprise the majority of cases.<h4>Methods</h4>To identify constitutional genetic variations contributing to ovarian cancer mortality, we systematically investigated associations between germline polymorphisms and ovarian cancer survival using data from The Cancer Genome Atlas Project (TCGA). Using stage-stratified Cox proportional hazards regression, we examined >650,000 SNP loci for association with survival. We additionally examined whether the association of significant SNPs with survival was modified by somatic alterations.<h4>Results</h4>Germline polymorphisms at rs4934282 (AGAP11/C10orf116) and rs1857623 (DNAH14) were associated with stage-adjusted survival (p= 1.12e-07 and 1.80e-07, FDR q= 1.2e-04 and 2.4e-04, respectively). A third SNP, rs4869 (C10orf116), was additionally identified as significant in the exome sequencing data; it is in near-perfect LD with rs4934282. The associations with survival remained significant when somatic alterations.<h4>Conclusions</h4>Discovery analysis of TCGA data reveals germline genetic variations that may play a role in ovarian cancer survival even among late-stage cases. The significant loci are located near genes previously reported as having a possible relationship to platinum and taxol response. Because the variant alleles at the significant loci are common (frequencies for rs4934282 A/C alleles = 0.54/0.46, respectively; rs1857623 A/G alleles = 0.55/0.45, respectively) and germline variants can be assayed noninvasively, our findings provide potential targets for further exploration as prognostic biomarkers and individualized therapies.
format	article
author	Rosemary Braun Richard Finney Chunhua Yan Qing-Rong Chen Ying Hu Michael Edmonson Daoud Meerzaman Kenneth Buetow
author_facet	Rosemary Braun Richard Finney Chunhua Yan Qing-Rong Chen Ying Hu Michael Edmonson Daoud Meerzaman Kenneth Buetow
author_sort	Rosemary Braun
title	Discovery analysis of TCGA data reveals association between germline genotype and survival in ovarian cancer patients.
title_short	Discovery analysis of TCGA data reveals association between germline genotype and survival in ovarian cancer patients.
title_full	Discovery analysis of TCGA data reveals association between germline genotype and survival in ovarian cancer patients.
title_fullStr	Discovery analysis of TCGA data reveals association between germline genotype and survival in ovarian cancer patients.
title_full_unstemmed	Discovery analysis of TCGA data reveals association between germline genotype and survival in ovarian cancer patients.
title_sort	discovery analysis of tcga data reveals association between germline genotype and survival in ovarian cancer patients.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/906954cf1fef46d280fd7e95b730f7cd
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Discovery analysis of TCGA data reveals association between germline genotype and survival in ovarian cancer patients.

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