Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling.

Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants of u...

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Autores principales:	Martin J Larsen, Torben A Kruse, Qihua Tan, Anne-Vibeke Lænkholm, Martin Bak, Anne E Lykkesfeldt, Kristina P Sørensen, Thomas V O Hansen, Bent Ejlertsen, Anne-Marie Gerdes, Mads Thomassen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4ccdc704eb1c4c9e9250ec9c36bbdad8
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spelling	oai:doaj.org-article:4ccdc704eb1c4c9e9250ec9c36bbdad82021-11-18T07:44:59ZClassifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling.1932-620310.1371/journal.pone.0064268https://doaj.org/article/4ccdc704eb1c4c9e9250ec9c36bbdad82013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23704984/?tool=EBIhttps://doaj.org/toc/1932-6203Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants of unclear pathogen significance are found in the families, constituting an increasing clinical challenge. New methods are therefore needed to improve the detection rate and aid the interpretation of the clinically uncertain variants. In this study we analyzed a series of 33 BRCA1, 22 BRCA2, and 128 sporadic tumors by RNA profiling to investigate the classification potential of RNA profiles to predict BRCA1/2 mutation status. We found that breast tumors from BRCA1 and BRCA2 mutation carriers display characteristic RNA expression patterns, allowing them to be distinguished from sporadic tumors. The majority of BRCA1 tumors were basal-like while BRCA2 tumors were mainly luminal B. Using RNA profiles, we were able to distinguish BRCA1 tumors from sporadic tumors among basal-like tumors with 83% accuracy and BRCA2 from sporadic tumors among luminal B tumors with 89% accuracy. Furthermore, subtype-specific BRCA1/2 gene signatures were successfully validated in two independent data sets with high accuracies. Although additional validation studies are required, indication of BRCA1/2 involvement ("BRCAness") by RNA profiling could potentially be valuable as a tool for distinguishing pathogenic mutations from benign variants, for identification of undetected mutation carriers, and for selecting patients sensitive to new therapeutics such as PARP inhibitors.Martin J LarsenTorben A KruseQihua TanAnne-Vibeke LænkholmMartin BakAnne E LykkesfeldtKristina P SørensenThomas V O HansenBent EjlertsenAnne-Marie GerdesMads ThomassenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 5, p e64268 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Martin J Larsen Torben A Kruse Qihua Tan Anne-Vibeke Lænkholm Martin Bak Anne E Lykkesfeldt Kristina P Sørensen Thomas V O Hansen Bent Ejlertsen Anne-Marie Gerdes Mads Thomassen Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling.
description	Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants of unclear pathogen significance are found in the families, constituting an increasing clinical challenge. New methods are therefore needed to improve the detection rate and aid the interpretation of the clinically uncertain variants. In this study we analyzed a series of 33 BRCA1, 22 BRCA2, and 128 sporadic tumors by RNA profiling to investigate the classification potential of RNA profiles to predict BRCA1/2 mutation status. We found that breast tumors from BRCA1 and BRCA2 mutation carriers display characteristic RNA expression patterns, allowing them to be distinguished from sporadic tumors. The majority of BRCA1 tumors were basal-like while BRCA2 tumors were mainly luminal B. Using RNA profiles, we were able to distinguish BRCA1 tumors from sporadic tumors among basal-like tumors with 83% accuracy and BRCA2 from sporadic tumors among luminal B tumors with 89% accuracy. Furthermore, subtype-specific BRCA1/2 gene signatures were successfully validated in two independent data sets with high accuracies. Although additional validation studies are required, indication of BRCA1/2 involvement ("BRCAness") by RNA profiling could potentially be valuable as a tool for distinguishing pathogenic mutations from benign variants, for identification of undetected mutation carriers, and for selecting patients sensitive to new therapeutics such as PARP inhibitors.
format	article
author	Martin J Larsen Torben A Kruse Qihua Tan Anne-Vibeke Lænkholm Martin Bak Anne E Lykkesfeldt Kristina P Sørensen Thomas V O Hansen Bent Ejlertsen Anne-Marie Gerdes Mads Thomassen
author_facet	Martin J Larsen Torben A Kruse Qihua Tan Anne-Vibeke Lænkholm Martin Bak Anne E Lykkesfeldt Kristina P Sørensen Thomas V O Hansen Bent Ejlertsen Anne-Marie Gerdes Mads Thomassen
author_sort	Martin J Larsen
title	Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling.
title_short	Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling.
title_full	Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling.
title_fullStr	Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling.
title_full_unstemmed	Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling.
title_sort	classifications within molecular subtypes enables identification of brca1/brca2 mutation carriers by rna tumor profiling.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/4ccdc704eb1c4c9e9250ec9c36bbdad8
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Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling.

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