Identification of a genomic signature in BRCA1-mutated triple negative breast cancer by Comparative Genomic Hybridization
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE54140 | GEO | 2015/12/10
SECONDARY ACCESSION(S): PRJNA235298
REPOSITORIES: GEO
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Project description:Determination of recurrent chromosomal aberrations in Luninal A, Luminal B, HER2-positve, and triple negative breast cancers 131 samples, Tumour DNA vs Normal DNA
2015-12-10 | E-GEOD-54140 | biostudies-arrayexpress
Project description:Breast cancer is a profoundly heterogeneous disease with respect to biological and clinical behavior. Gene expression profiling has been used to dissect this complexity and stratify tumors into intrinsic gene expression subtypes associated with distinct biology, patient outcome and different genomic alterations. Additionally, breast tumors occurring in individuals with germline BRCA1 or BRCA2 mutations typically fall into distinct subtypes. We applied global DNA copy number and gene expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy number aberrations and genomic subgroups of breast cancer. We identified 31 genomic regions that were highly amplified in >1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions (66 and 67 with DNA copy number gain and loss, respectively) revealed six genomic subtypes, termed: 17q12, basal-complex, luminal-simple, luminal-complex, amplifier and mixed subtype. Four of them had striking similarity to intrinsic gene expression subtypes and showed association to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having better prognosis while the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors from all gene expression subtypes, the former being enriched for 8p12-amplified cases while the mixed subtype included many tumors with predominantly DNA copy number losses and poor prognosis.
2010-06-24 | GSE22133 | GEO
Project description:Breast cancer is a profoundly heterogeneous disease with respect to biological and clinical behavior. Gene expression profiling has been used to dissect this complexity and stratify tumors into intrinsic gene expression subtypes associated with distinct biology, patient outcome and different genomic alterations. Additionally, breast tumors occurring in individuals with germline BRCA1 or BRCA2 mutations typically fall into distinct subtypes. We applied global DNA copy number and gene expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy number aberrations and genomic subgroups of breast cancer. We identified 31 genomic regions that were highly amplified in >1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions (66 and 67 with DNA copy number gain and loss, respectively) revealed six genomic subtypes, termed: 17q12, basal-complex, luminal-simple, luminal-complex, amplifier and mixed subtype. Four of them had striking similarity to intrinsic gene expression subtypes and showed association to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having better prognosis while the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors from all gene expression subtypes, the former being enriched for 8p12-amplified cases while the mixed subtype included many tumors with predominantly DNA copy number losses and poor prognosis. Genomic profiling of 359 breast tumors using tiling BAC aCGH. A number of cases were hybridized as replicates or replicate as dye-swaps. Gene expression profiling of 359 breast tumors using 55K oligonucleotide microarrays.
2010-06-23 | E-GEOD-22133 | biostudies-arrayexpress
Project description:Triple Negative Breast Cancers (TNBC) represent about 12% to 20% of all breast cancers (BC) and have a worse outcome compared to other BC subtypes. TNBC often show a deficiency in DNA double-strand break repair mechanisms. This is generally related to the inactivation of a repair enzymatic complex involving BRCA1 caused either by genetic mutations, epigenetic modifications or by post-transcriptional regulations. The identification of new molecular biomarkers that would allow the rapid identification of BC presenting a BRCA1 deficiency could be useful to select patients who could benefit from PARP inhibitors, alkylating agents or platinum-based chemotherapy.Genomic DNA from 131 formalin-fixed paraffin-embedded (FFPE) tumors (luminal A and B, HER2+ and triple negative BC) with known BRCA1 mutation status or unscreened for BRCA1 mutation were analysed by array Comparative Genomic Hybridization (array CGH). One highly significant and recurrent gain in the 17q25.3 genomic region was analysed by fluorescent in situ hybridization (FISH). Expression of the genes of the 17q25.3 amplicon was studied using customized Taqman low density arrays and single Taqman assays (Applied Biosystems).We identified by array CGH and confirmed by FISH a gain in the 17q25.3 genomic region in 90% of the BRCA1 mutated tumors. This chromosomal gain was present in only 28.6% of the BRCA1 non-mutated TNBC, 26.7% of the unscreened TNBC, 13.6% of the luminal B, 19.0% of the HER2+ and 0% of the luminal A breast cancers. The 17q25.3 gain was also detected in 50% of the TNBC with BRCA1 promoter methylation. Interestingly, BRCA1 promoter methylation was never detected in BRCA1 mutated BC. Gene expression analyses of the 17q25.3 sub-region showed a significant over-expression of 17 genes in BRCA1 mutated TNBC (n?=?15) as compared to the BRCA1 non mutated TNBC (n?=?13).In this study, we have identified by array CGH and confirmed by FISH a recurrent gain in 17q25.3 significantly associated to BRCA1 mutated TNBC. Up-regulated genes in the 17q25.3 amplicon might represent potential therapeutic targets and warrant further investigation.
| S-EPMC4303204 | biostudies-literature
Project description:Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.
| S-EPMC7385112 | biostudies-literature
Project description:Breast cancer is a heterogeneous disease comprised of four molecular subtypes defined by whether the tumor-originating cells are luminal or basal epithelial cells. Breast cancers arising from the luminal mammary duct often express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2). Tumors expressing ER and/or PR are treated with anti-hormonal therapies, while tumors overexpressing HER2 are targeted with monoclonal antibodies. Immunohistochemical detection of ER, PR, and HER2 receptors/proteins is a critical step in breast cancer diagnosis and guided treatment. Breast tumors that do not express these proteins are known as “triple negative breast cancer” (TNBC) and are typically basal-like. TNBCs are the most aggressive subtype, with the highest mortality rates and no targeted therapy, so there is a pressing need to identify important TNBC tumor regulators. The signal transducer and activator of transcription 3 (STAT3) transcription factor has been previously implicated as a constitutively active oncogene in TNBC. However, its direct regulatory gene targets and tumorigenic properties have not been well characterized. By integrating RNA-seq and ChIP-seq data from 2 TNBC tumors and 4 cell lines, we discovered novel gene signatures directly regulated by STAT3 that were enriched for processes involving inflammation, immunity, and invasion in TNBC. Functional analysis revealed that STAT3 has a key role regulating invasion and metastasis, a characteristic often associated with TNBC. Our findings suggest therapies targeting STAT3 may be important for preventing TNBC metastasis.
2017-06-10 | GSE85579 | GEO
Project description:Triple-negative (TN) and Basal-like (BL) breast cancer definitions have been used interchangeably to identify breast cancers that lack expression of the hormonal receptors (HR) and overexpression and/or amplification of HER2. However, both classifications when compared to each other, show substantial discordance rates. Here, we molecularly characterize TN tumors, and Basal-like tumors, and compare and contrast the results in terms of common patterns and distinct patterns for each. In total, when testing 412 TN and 473 Basal-like tumors, 21.4% and 31.5% were identified as non-Basal-like and non-TN, respectively. TN tumors identified as Luminal or HER2-enriched showed undistinguishable overall gene expression profiles when compared versus Luminal or HER2-enriched tumors that were not TN. Similar findings were observed within Basal-like tumors regardless of the TN status. Interestingly, most TN tumors identified as HER2-enriched showed low HER2 expression and lack of HER2 amplification despite the similar overall gene expression profiles to HER2-E tumors that were not TN. Lastly, additional genomic classifications are examined within TN and Basal-like cancers, most of which are largely concordant with tumor intrinsic subtype. These results suggest that future clinical trials focused on TN disease should consider stratifying patients based on Basal-like versus non-Basal-like gene expression profiles as this appears to be the main biological difference seen within TN breast cancer patients. reference x sample
2014-07-29 | E-GEOD-41119 | biostudies-arrayexpress
Project description:Triple-negative (TN) and Basal-like (BL) breast cancer definitions have been used interchangeably to identify breast cancers that lack expression of the hormonal receptors (HR) and overexpression and/or amplification of HER2. However, both classifications when compared to each other, show substantial discordance rates. Here, we molecularly characterize TN tumors, and Basal-like tumors, and compare and contrast the results in terms of common patterns and distinct patterns for each. In total, when testing 412 TN and 473 Basal-like tumors, 21.4% and 31.5% were identified as non-Basal-like and non-TN, respectively. TN tumors identified as Luminal or HER2-enriched showed undistinguishable overall gene expression profiles when compared versus Luminal or HER2-enriched tumors that were not TN. Similar findings were observed within Basal-like tumors regardless of the TN status. Interestingly, most TN tumors identified as HER2-enriched showed low HER2 expression and lack of HER2 amplification despite the similar overall gene expression profiles to HER2-E tumors that were not TN. Lastly, additional genomic classifications are examined within TN and Basal-like cancers, most of which are largely concordant with tumor intrinsic subtype. These results suggest that future clinical trials focused on TN disease should consider stratifying patients based on Basal-like versus non-Basal-like gene expression profiles as this appears to be the main biological difference seen within TN breast cancer patients.
2014-07-29 | GSE41119 | GEO
Project description:While new defects in BRCA1 are still being found, it is unclear whether current breast cancer diagnostics misses many BRCA1-associated cases. A reliable test that is able to indicate the involvement of BRCA1 deficiency in cancer genesis could support decision making in genetic counselling and clinical management. To find BRCA1-specific markers and explore the effectiveness of the current diagnostic strategy, we designed a classification method, validated it and examined whether we could find BRCA1-like breast tumours in a group of patients initially diagnosed as non-BRCA1/2 mutation carriers. A classifier was built based on array-CGH profiles of 18 BRCA1-related and 32 control breast tumours, and validated on independent sets of 16 BRCA1-related and 16 control breast carcinomas. Subsequently, we applied the classifier to 48 breast tumours of patients from Hereditary Breast and Ovarian Cancer (HBOC) families in whom no germ line BRCA1/BRCA2 mutations were identified. The classifier showed an accuracy of 91% when applied to the validation sets. In 48 non-BRCA1/2 patients, only two breast tumours presented a BRCA1-like CGH profile. Additional evidence for BRCA1 dysfunction was found in one of these tumours. We here describe the specific chromosomal aberrations in BRCA1-related breast carcinomas. We developed a predictive genetic test for BRCA1-association and show that BRCA1-related tumours can still be identified in HBOC families after routine DNA diagnostics.
2010-12-02 | GSE9021 | GEO
Project description:We report a deep next-generation sequencing analysis of 13 sequentially obtained tumor samples, eight sequentially obtained circulating tumor DNA (ctDNA) samples and three germline DNA samples over the life history of 3 patients with triple-negative breast cancer (TNBC), 2 of whom had germline pathogenic BRCA1 mutation, to unravel tumor evolution. Tumor tissue from all timepoints and germline DNA was subjected to whole-exome sequencing (WES), custom amplicon deep sequencing (30,000X) of a WES-derived somatic mutation panel, and SNP arrays for copy-number variation (CNV), while whole transcriptome sequencing (RNA-seq) was performed only on somatic tumor.There was enrichment of homologous recombination deficiency signature in all tumors and widespread CNV, which remained largely stable over time. Somatic tumor mutation numbers varied between patients and within each patient (range: 70-216, one outlier). There was minimal mutational overlap between patients with TP53 being the sole commonly mutated gene, but there was substantial overlap in sequential samples in each patient. Each patient's tumor contained a founding ("stem") clone at diagnosis, which persisted over time, from which all other clones ("subclone") were derived ("branching evolution"), which contained mutations in well-characterized cancer-related genes like PDGFRB, ARID2, TP53 (Patient_02), TP53, BRAF, BRIP1, CSF3R (Patient_04), and TP53, APC, EZH2 (Patient_07). Including stem and subclones, tumors from all patients were polyclonal at diagnosis and during disease progression. ctDNA recapitulated most tissue-derived stem clonal and subclonal mutations while detecting some additional subclonal mutations. RNA-seq revealed a stable basal-like pattern, with most highly expressed variants belonging to stem clone.SignificanceIn germline BRCA1 mutated and BRCA wild-type patients, TNBC shows a branching evolutionary pattern of mutations with a single founding clone, are polyclonal throughout their disease course, and have widespread copy-number aberrations. This evolutionary pattern may be associated with treatment resistance or sensitivity and could be therapeutically exploited.
| S-EPMC10865976 | biostudies-literature