Dataset Information

Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy.

ABSTRACT:

Introduction

BRCA-mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating agents and platinum salts. HRD can be caused by BRCA mutations, and by other mechanisms. To identify HRD, studies have focused on triple-negative (TN) breast cancers as these resemble BRCA1-mutated breast cancer closely and might also share this hypersensitivity. However, ways to identify HRD in non-BRCA-mutated, estrogen receptor (ER)-positive breast cancers have remained elusive. The current study provides evidence that genomic patterns resembling BRCA1- or BRCA2-mutated breast cancers can identify breast cancer patients with TN as well as ER-positive, HER2-negative tumors that are sensitive to intensified, DSB-inducing chemotherapy.

Methods

Array comparative genomic hybridization (aCGH) was used to classify breast cancers. Patients with tumors with similar aCGH patterns as BRCA1- and/or BRCA2-mutated breast cancers were defined as having a BRCA-likeCGH status, others as non-BCRA-likeCGH. Stage-III patients (n?=?249) had participated in a randomized controlled trial of adjuvant high-dose (HD) cyclophosphamide-thiotepa-carboplatin (CTC) versus 5-fluorouracil-epirubicin-cyclophosphamide (FE90C) chemotherapy.

Results

Among patients with BRCA-likeCGH tumors (81/249, 32%), a significant benefit of HD-CTC compared to FE90C was observed regarding overall survival (adjusted hazard ratio 0.19, 95% CI: 0.08 to 0.48) that was not seen for patients with non-BRCA-likeCGH tumors (adjusted hazard ratio 0.90, 95% CI: 0.53 to 1.54) (P?=?0.004). Half of all BRCA-likeCGH tumors were ER-positive.

Conclusions

Distinct aCGH patterns differentiated between HER2-negative patients with a markedly improved outcome after adjuvant treatment with an intensified DNA-DSB-inducing regimen (BRCA-likeCGH patients) and those without benefit (non-BRCA-likeCGH patients).

SUBMITTER: Vollebergh MA

PROVIDER: S-EPMC4076636 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy.

Vollebergh Marieke A MA Lips Esther H EH Nederlof Petra M PM Wessels Lodewyk F A LF Wesseling Jelle J Vd Vijver Marc J MJ de Vries Elisabeth G E EG van Tinteren Harm H Jonkers Jos J Hauptmann Michael M Rodenhuis Sjoerd S Linn Sabine C SC

Breast cancer research : BCR 20140515 3

<h4>Introduction</h4>BRCA-mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating agents and platinum salts. HRD can be caused by BRCA mutations, and by other mechanisms. To identify HRD, studies have focused on triple-negative (TN) breast cancers as these resemble BRCA1-mu ...[more]

PMID: 24887359

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Project description:BACKGROUND: Genomic gains and losses are a result of genomic instability in many types of cancers. BRCA1- and BRCA2-mutated breast cancers are associated with increased amounts of chromosomal aberrations, presumably due their functions in genome repair. Some of these genomic aberrations may harbor genes whose absence or overexpression may give rise to cellular growth advantage. So far, it has not been easy to identify the driver genes underlying gains and losses. A powerful approach to identify these driver genes could be a cross-species comparison of array comparative genomic hybridization (aCGH) data from cognate mouse and human tumors. Orthologous regions of mouse and human tumors that are commonly gained or lost might represent essential genomic regions selected for gain or loss during tumor development. METHODS: To identify genomic regions that are associated with BRCA1- and BRCA2-mutated breast cancers we compared aCGH data from 130 mouse Brca1?/?;p53?/?, Brca2?/?;p53?/? and p53?/? mammary tumor groups with 103 human BRCA1-mutated, BRCA2-mutated and non-hereditary breast cancers. RESULTS: Our genome-wide cross-species analysis yielded a complete collection of loci and genes that are commonly gained or lost in mouse and human breast cancer. Principal common CNAs were the well known MYC-associated gain and RB1/INTS6-associated loss that occurred in all mouse and human tumor groups, and the AURKA-associated gain occurred in BRCA2-related tumors from both species. However, there were also important differences between tumor profiles of both species, such as the prominent gain on chromosome 10 in mouse Brca2?/?;p53?/? tumors and the PIK3CA associated 3q gain in human BRCA1-mutated tumors, which occurred in tumors from one species but not in tumors from the other species. This disparity in recurrent aberrations in mouse and human tumors might be due to differences in tumor cell type or genomic organization between both species. CONCLUSIONS: The selection of the oncogenome during mouse and human breast tumor development is markedly different, apart from the MYC gain and RB1-associated loss. These differences should be kept in mind when using mouse models for preclinical studies.

Project description:Molecular Profiling of BRCA1-and BRCA2-associated Breast Cancers Identifies FGFR2 as a Gene More Highly Expressed in BRCA2-associated Tumors BRCA1- and BRCA2-associated tumors have many morphologic characteristics in common, but appear to have distinct molecular signatures. BRCA1-associated tumors are predominantly basal-like cancers, whereas BRCA2-associated tumors have a predominant luminal-like phenotype. These two molecular signatures reflect in part the two cell types, basal/myoepithelial and luminal, found in the terminal duct lobular unit of the breast. To elucidate novel genes involved in these two spectra of breast cancer tumorigenesis we performed global gene expression analysis on breast tumors from germline BRCA1 and BRCA2 mutation carriers. Breast tumor RNAs from 7 germline BRCA1 and 6 germline BRCA2 carriers were profiled using UHN human 19K cDNA microarrays. Supervised univariate analyses were conducted to identify genes differentially expressed between BRCA1 and BRCA2-associated tumors. Selected discriminatory genes were validated using real time reverse transcription polymerase chain reaction (RT-PCR) in the tumor RNAs, and/or by immunohistochemistry (IHC) or by in situ hybridization (ISH) on tissue microarrays (TMAs) containing an independent set of 58 BRCA1 and 64 BRCA2-associated tumors. Genes more highly expressed in BRCA1-associated tumors included stathmin/oncoprotein 18, osteopontin, TGFß2 and Jagged 1 in addition to genes previously identified as characteristic of basal-like breast cancers. Genes more highly expressed in BRCA2-associated tumors had functions related to transcription, signal transduction (particularly MAPK signaling), cell proliferation, cell adhesion and extracellular matrix remodeling. BRCA2-associated cancers were characterized by the higher relative expression of amongst others, FGF1 and FGFR2. Tissue microarrays were used to validate the expression of FGFR2 protein by immunohistochemistry and Jagged 1 expression by in situ hybridization. BRCA2-associated cancers expressed higher levels of FGFR2 protein than BRCA1-associated cancers (p=0.004); whereas BRCA1-associated tumors exhibited elevated levels of Jagged1 mRNA compared to BRCA2-associated cancers (p=0.02). FGFR2 and FGF1 were more highly expressed in BRCA2-associated cancers compared with BRCA1-associated breast cancers, suggesting the existence of an autocrine or paracrine stimulatory loop. In addition to corroborating the basal-like signature of BRCA1-associated tumors, we identified osteopontin, stathmin/oncoprotein 18, TGFβ2, and Jagged 1 as being more highly expressed in BRCA1-associated tumors. Keywords: Gene expression profiling, genetic comparison

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Dataset Information

Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy.

Introduction

Methods

Results

Conclusions

Publications

Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy.

Similar Datasets

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