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Genomic and phenotypic analysis of BRCA2 mutated breast cancers reveals co-occurring changes linked to progression
BACKGROUND: Inherited mutations in the BRCA2 gene greatly increase the risk of developing breast cancer. Consistent with an important role for BRCA2 in error-free DNA repair, complex genomic changes are frequently observed in tumors derived from BRCA2 mutation carriers. Here, we explore the impact o...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262207/ https://www.ncbi.nlm.nih.gov/pubmed/21958427 http://dx.doi.org/10.1186/bcr3020 |
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author | Stefansson, Olafur A Jonasson, Jon G Olafsdottir, Kristrun Bjarnason, Hordur Th Johannsson, Oskar Bodvarsdottir, Sigridur K Valgeirsdottir, Sigridur Eyfjord, Jorunn E |
author_facet | Stefansson, Olafur A Jonasson, Jon G Olafsdottir, Kristrun Bjarnason, Hordur Th Johannsson, Oskar Bodvarsdottir, Sigridur K Valgeirsdottir, Sigridur Eyfjord, Jorunn E |
author_sort | Stefansson, Olafur A |
collection | PubMed |
description | BACKGROUND: Inherited mutations in the BRCA2 gene greatly increase the risk of developing breast cancer. Consistent with an important role for BRCA2 in error-free DNA repair, complex genomic changes are frequently observed in tumors derived from BRCA2 mutation carriers. Here, we explore the impact of DNA copy-number changes in BRCA2 tumors with respect to phenotype and clinical staging of the disease. METHODS: Breast tumors (n = 33) derived from BRCA2 999del5 mutation carriers were examined in terms of copy-number changes with high-resolution aCGH (array comparative genomic hybridization) containing 385 thousand probes (about one for each 7 kbp) and expression of phenotypic markers on TMAs (tissue microarrays). The data were examined with respect to clinical parameters including TNM staging, histologic grade, S phase, and ploidy. RESULTS: Tumors from BRCA2 carriers of luminal and basal/triple-negative phenotypes (TNPs) differ with respect to patterns of DNA copy-number changes. The basal/TNP subtype was characterized by lack of pRb (RB1) coupled with high/intense expression of p16 (CDKN2A) gene products. We found increased proportions of Ki-67-positive cells to be significantly associated with loss of the wild-type (wt) BRCA2 allele in luminal types, whereas BRCA2wt loss was less frequent in BRCA2 tumors displaying basal/TNP phenotypes. Furthermore, we show that deletions at 13q13.1, involving the BRCA2wt allele, represents a part of a larger network of co-occurring genetic changes, including deletions at 6q22.32-q22.33, 11q14.2-q24.1, and gains at 17q24.1. Importantly, copy-number changes at these BRCA2-linked networking regions coincide with those associated with advanced progression, involving the capacity to metastasize to the nodes or more-distant sites at diagnosis. CONCLUSIONS: The results presented here demonstrate divergent paths of tumor evolution in BRCA2 carriers and that deletion of the wild-type BRCA2 allele, together with co-occurring changes at 6 q, 11 q, and 17 q, are important events in progression toward advanced disease. |
format | Online Article Text |
id | pubmed-3262207 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-32622072012-01-20 Genomic and phenotypic analysis of BRCA2 mutated breast cancers reveals co-occurring changes linked to progression Stefansson, Olafur A Jonasson, Jon G Olafsdottir, Kristrun Bjarnason, Hordur Th Johannsson, Oskar Bodvarsdottir, Sigridur K Valgeirsdottir, Sigridur Eyfjord, Jorunn E Breast Cancer Res Research Article BACKGROUND: Inherited mutations in the BRCA2 gene greatly increase the risk of developing breast cancer. Consistent with an important role for BRCA2 in error-free DNA repair, complex genomic changes are frequently observed in tumors derived from BRCA2 mutation carriers. Here, we explore the impact of DNA copy-number changes in BRCA2 tumors with respect to phenotype and clinical staging of the disease. METHODS: Breast tumors (n = 33) derived from BRCA2 999del5 mutation carriers were examined in terms of copy-number changes with high-resolution aCGH (array comparative genomic hybridization) containing 385 thousand probes (about one for each 7 kbp) and expression of phenotypic markers on TMAs (tissue microarrays). The data were examined with respect to clinical parameters including TNM staging, histologic grade, S phase, and ploidy. RESULTS: Tumors from BRCA2 carriers of luminal and basal/triple-negative phenotypes (TNPs) differ with respect to patterns of DNA copy-number changes. The basal/TNP subtype was characterized by lack of pRb (RB1) coupled with high/intense expression of p16 (CDKN2A) gene products. We found increased proportions of Ki-67-positive cells to be significantly associated with loss of the wild-type (wt) BRCA2 allele in luminal types, whereas BRCA2wt loss was less frequent in BRCA2 tumors displaying basal/TNP phenotypes. Furthermore, we show that deletions at 13q13.1, involving the BRCA2wt allele, represents a part of a larger network of co-occurring genetic changes, including deletions at 6q22.32-q22.33, 11q14.2-q24.1, and gains at 17q24.1. Importantly, copy-number changes at these BRCA2-linked networking regions coincide with those associated with advanced progression, involving the capacity to metastasize to the nodes or more-distant sites at diagnosis. CONCLUSIONS: The results presented here demonstrate divergent paths of tumor evolution in BRCA2 carriers and that deletion of the wild-type BRCA2 allele, together with co-occurring changes at 6 q, 11 q, and 17 q, are important events in progression toward advanced disease. BioMed Central 2011 2011-09-29 /pmc/articles/PMC3262207/ /pubmed/21958427 http://dx.doi.org/10.1186/bcr3020 Text en Copyright ©2011 Stefansson et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Stefansson, Olafur A Jonasson, Jon G Olafsdottir, Kristrun Bjarnason, Hordur Th Johannsson, Oskar Bodvarsdottir, Sigridur K Valgeirsdottir, Sigridur Eyfjord, Jorunn E Genomic and phenotypic analysis of BRCA2 mutated breast cancers reveals co-occurring changes linked to progression |
title | Genomic and phenotypic analysis of BRCA2 mutated breast cancers reveals co-occurring changes linked to progression |
title_full | Genomic and phenotypic analysis of BRCA2 mutated breast cancers reveals co-occurring changes linked to progression |
title_fullStr | Genomic and phenotypic analysis of BRCA2 mutated breast cancers reveals co-occurring changes linked to progression |
title_full_unstemmed | Genomic and phenotypic analysis of BRCA2 mutated breast cancers reveals co-occurring changes linked to progression |
title_short | Genomic and phenotypic analysis of BRCA2 mutated breast cancers reveals co-occurring changes linked to progression |
title_sort | genomic and phenotypic analysis of brca2 mutated breast cancers reveals co-occurring changes linked to progression |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262207/ https://www.ncbi.nlm.nih.gov/pubmed/21958427 http://dx.doi.org/10.1186/bcr3020 |
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