Abstract
BackgroundInherited 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.MethodsBreast 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.ResultsTumors 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.ConclusionsThe 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.
Highlights
Germline mutations in one allele of the BRCA2 tumorsuppressor gene confer greatly increased risk of developing breast cancer [1]
To follow up on these results, we have studied copy-number changes in a larger number of BRCA2 tumors by high-resolution array-comparative hybridization microarrays containing 385 thousand probes in breast tumors derived from BRCA2 germline mutation carriers (n = 33) combined with analysis of phenotypic markers by immunohistochemistry (IHC) on tissue microarrays (TMAs)
Breast cancer subtypes in BRCA2 mutated tumors Thirty-three female breast cancer patients carrying the same 999del5 BRCA2 germline mutation constituted the study group analyzed with array comparative genomic hybridization (CGH)
Summary
Germline mutations in one allele of the BRCA2 tumorsuppressor gene confer greatly increased risk of developing breast cancer [1]. The LumB subtype differs from LumA by high expression of proliferation-associated genes with increased levels of MKI67 (Ki-67) as a prominent feature, and are associated with less-favorable disease outcome [12]. Tumors arising in BRCA2 germline mutation carriers mostly display luminal phenotypes of high histologic grade and have prominent expression of proliferation markers, suggesting similarities to the LumB subtype [14]. To follow up on these results, we have studied copy-number changes in a larger number of BRCA2 tumors by high-resolution array-comparative hybridization (aCGH) microarrays containing 385 thousand probes (about one for each 7 kbp) in breast tumors derived from BRCA2 germline mutation carriers (n = 33) combined with analysis of phenotypic markers by immunohistochemistry (IHC) on tissue microarrays (TMAs). We explore the impact of DNA copy-number changes in BRCA2 tumors with respect to phenotype and clinical staging of the disease
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
