DNA methylome of familial breast cancer identifies distinct profiles defined by mutation status
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE17125 | GEO | 2010/03/12
SECONDARY ACCESSION(S): PRJNA119727
REPOSITORIES: GEO
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Project description:About 25% of familial breast cancer (BC) is attributed to germline mutations of BRCA1 and BRCA2 genes while the rest of patients are included in the BRCAX group. BC also affects men with a worldwide incidence of 1%. The epigenetic alterations, including those DNA methylation, have been rarely studied in the male breast cancer (MBC) on a genome-wide level. The aim of the current work was to study the global DNA methylation profiles of BC patients to look for differences between familial female breast cancer (FBC) and MBC and according to BRCA1, BRCA2 and BRCAX mutation status. The genomic DNA from FFPE tissues of 17 female and 7 male patients with BC was subjected to methylated DNA immunoprecipitation (MeDIP) and hybridized on human promoter microarrays. The comparison between FBC and MBC showed 2846 differentially methylated regions (DMRs) corresponding to 2486 distinct annotated genes. The gene ontology enrichment analysis revealdrelevant molecular function terms such as the GTPase superfamily genes (in particular the GTPase Rho GAP/GEF and GTPase RAB) and cellular component terms associated to cytoskeletal architecture such as “cytoskeletal part”, “keratin filament”, “intermediate filament". By considering only FBC, several cancer-associated pathways were the most enriched KEGG pathways of differentially methylated genes between BRCA2 and BRCAX or BRCA1+BRCAX groups. The comparison between BRCA1 group vs BRCA2+BRCAX group displayed the enriched molecular function term “cytoskeletal protein binding”. Finally, the functional annotation of differentially methylated genes between BRCAX and BRCA1+BRCA2 groups indicated that the most enriched molecular function terms were related to GTPase activity. In summary, this is the first study that compares the global DNA methylation profile of familial FBC and MBC and the results may provide useful insights into the epigenomic subtyping of breast cancer and shed light on a possible new molecular mechanisms underlying BC carcinogenesis.
2020-07-02 | GSE153636 | GEO
Project description:Use of DNA damaging agents and RNA pooling to assess expression profiles associated with BRCA1 and BRCA2 mutation status in familial breast cancer patients Background: A large number of rare sequence variants of unknown clinical significance have been identified in the breast cancer susceptibility genes, BRCA1 and BRCA2. Determining the functional effect of these variants as well as their role in breast cancer susceptibility can be challenging using current classification methods. Methodology/Principal Findings: To identify predictors of pathogenic mutation status in familial breast cancer patients, we explored the use of gene expression arrays to assess the effect of two DNA damaging agents (irradiation and mitomycin C) on cellular response in relation to BRCA1 and BRCA2 mutation status. A range of regimes were used to treat 27 lymphoblastoid cell-lines (LCLs) derived from affected women in high-risk breast cancer families (nine BRCA1, nine BRCA2, and nine non-BRCA1/2 or BRCAX individuals) and nine LCLs from healthy individuals. Using an RNA pooling strategy, we found that treating LCLs with 1.2 μM mitomycin C and measuring the gene expression profiles 1 hour post-treatment had the greatest potential to discriminate BRCA1, BRCA2 and BRCAX mutation status. A classifier was built using the expression profile of nine QRT-PCR validated genes that were associated with BRCA1, BRCA2 and BRCAX status in RNA pools. These nine genes could distinguish BRCA1 from BRCA2 carriers with 83% accuracy in individual samples, but three-way analysis for BRCA1, BRCA2 and BRCAX had a maximum of 59% prediction accuracy. Conclusions/Significance: Our results suggest that, compared to BRCA1 and BRCA2 mutation carriers, non-BRCA1/2 (BRCAX) individuals are genetically heterogeneous. This study also demonstrates the effectiveness of RNA pools to compare the expression profiles of cell-lines from BRCA1, BRCA2 and BRCAX cases after treatment with irradiation and mitomycin C as a method to prioritize treatment regimes for detailed downstream expression analysis.
2010-01-20 | GSE17764 | GEO
Project description:In this study, using microarray technology we did a transcriptome profiling of miRNAs on a group of 52 cases of familial (BRCA1- or BRCA2-mutated, or BRCAX, i.e. familial cases with no mutations in BRCA1 or BRCA2 genes) and sporadic breast cancers. Class comparison of different clinical characteristics of the samples identified miR-342 as the miRNA with the most significant association with estrogen receptor (ER) status (categorised as positive and negative) of the samples analysed. As ER is one of the bio-pathological features currently used in routine clinical practice to aid treatment decision in breast cancer, identification of this miRNA has been promising for finding new mechanisms involved in this tumour type as we had next demonstrated in a cellular model of breast cancer.
2014-05-14 | GSE46966 | GEO
Project description:In this study, using microarray technology we did a transcriptome profiling of miRNAs on a group of 52 cases of familial (BRCA1- or BRCA2-mutated, or BRCAX, i.e. familial cases with no mutations in BRCA1 or BRCA2 genes) and sporadic breast cancers. Class comparison of different clinical characteristics of the samples identified miR-342 as the miRNA with the most significant association with estrogen receptor (ER) status (categorised as positive and negative) of the samples analysed. As ER is one of the bio-pathological features currently used in routine clinical practice to aid treatment decision in breast cancer, identification of this miRNA has been promising for finding new mechanisms involved in this tumour type as we had next demonstrated in a cellular model of breast cancer. In the study presented here, microRNAs expression profiling on a well defined cohort of 52 breast cancer cases, followed up for more than 5 years, was used for a class comparison analysis with some relevant clinical characteristics of this tumour type like estrogen, progesterone or epidermal growth factor 2 receptor status.
2014-05-14 | E-GEOD-46966 | biostudies-arrayexpress
Project description:Only about 25% of familial breast cancer is explained by mutations in BRCA1 and BRCA2, fewer by moderate penetrance genes like P53, PTEN, CHEK2, ATM and PALB2 and an unknown fraction by common variants of genes with low penetrance. Evidence suggests that additional dominant breast cancer genes exist and these are referred to as BRCAX. Clinical presentation of families with highly increased incidence of breast cancer that are non-BRCA1/BRCA2, suggests dominant inheritance of such high penetrance breast cancer genes. Because cancer genes often confer a specific clinical presentation (e.g. age of onset, sex-ratio, tissue spectrum) it seems useful to initiate their discovery by such clinical criteria. An earlier linkage study of BRCAX / non-BRCA1/2 breast cancer families aimed to enrich for a common genetic defect by setting stringent inclusion criteria, failed to identify new breast cancer susceptibility loci. Motivated by results of BRCA1 and BRCA2 breast tumors that have characteristic genomic signatures (array-CGH 'phenotypes'), we present the largest dataset to date showing the genomic profiles of 58 BRCAX primary breast tumors by array-CGH and show by unsupervised hierarchical clustering that they form a heterogeneous group with 4 distinct subtypes that are different from (n = 48) sporadic controls. This provides a possible explanation for the lack of high LOD scores in linkage studies. The presence of more than one BRCAX sub-type suggests the existence of more than one BRCAX gene. We propose approaches that can be employed to stratify BRCAX families based on array-CGH data. 58 primary breast carcinomas from non-BRCA1/2 hereditary breast cancer families (HBC) compared to 48 sporadic tumors
2011-02-01 | E-GEOD-18626 | biostudies-arrayexpress
Project description:Approximately 25% of hereditary breast cancer cases associated with a strong familial history can be explained by mutations in BRCA1 or BRCA2 and other lower penetrance genes. The remaining high-risk families could be classified as BRCAX (non-BRCA1/2) families, in which no penetrant mutation has been found until now. Gene expression involving alternative splicing represents a well-known mechanism regulating the expression of multiple transcripts encoded by individual genes, which could be involved in cancer development. Thus using RNA-seq methodology, the analysis of transcriptome in immortalized lymphoblastoid cell lines of high-risk breast cancer individuals could reveal transcripts implicated in breast cancer susceptibility and development. RNA was extracted from immortalized lymphoblastoid cell lines of 117 women (affected and unaffected) coming from BRCA1, BRCA2 and BRCAX families. Anova analysis revealed a total of 95 transcripts corresponding to 85 different genes differentially expressed (Bonferroni corrected p-value <0.01) between those groups. Hierarchical clustering allowed distinctive subgrouping of BRCA1/2 subgroups from BRCAX individuals, without regard for the cancer status. We found enrichment for pathways in signaling cascades including mTOR and EIF2-related pathways. No transcripts were differentially expressed between BRCA1 and BRCA2 individuals, however out of 95 transcripts, 67 could discriminate BRCAX from combination of BRCA1 and BRCA2 individuals. On the other hand, 28 transcripts could discriminate affected from unaffected BRCAX individuals. These BRCAX-associated transcripts demonstrated enrichment in Telomere Extension by Telomerase and Double-Strand Break Repair by Non-Homologous End Joining mechanisms. To our knowledge, this represents the first study identifying transcripts differentially expressed in immortalized lymphoblastoid cell lines coming from the major classes of mutation-related breast cancer subgroups, namely BRCA1, BRCA2 and BRCAX. Moreover, some transcripts could discriminate affected from unaffected BRCAX individuals, which could represent potential therapeutic targets for breast cancer treatment.
2019-09-30 | GSE87080 | GEO
Project description:The functional consequences of missense variants in disease genes are difficult to predict. We assessed if gene expression profiles could distinguish between BRCA1 or BRCA2 pathogenic truncating and missense mutation carriers and familial breast cancer cases whose disease was not attributable to BRCA1 or BRCA2 mutations (BRCAX cases). 72 cell lines from affected women in high-risk breast-ovarian families were assayed after exposure to ionising irradiation, including 23 BRCA1 carriers, 22 BRCA2 carriers, and 27 BRCAX individuals. A subset of 10 BRCAX individuals carried rare BRCA1/2 sequence variants considered to be of low clinical significance (LCS). BRCA1 and BRCA2 mutation carriers had similar expression profiles, with some subclustering of missense mutation carriers. The majority of BRCAX individuals formed a distinct cluster, but BRCAX individuals with LCS variants had expression profiles similar to BRCA1/2 mutation carriers. Gaussian Process Classifier predicted BRCA1, BRCA2 and BRCAX status with a maximum of 62% accuracy, and prediction accuracy decreased with inclusion of BRCAX samples carrying an LCS variant, and inclusion of pathogenic missense carriers. Similarly, prediction of mutation status with gene lists derived using Support Vector Machines was good for BRCAX samples without an LCS variant (82-94%), poor for BRCAX with an LCS (40-50%), and improved for pathogenic BRCA1/2 mutation carriers when the gene list used for prediction was appropriate to mutation effect being tested (71-100%). This study indicates that mutation effect, and presence of rare variants possibly associated with a low risk of cancer, must be considered in the development of array-based assays of variant pathogenicity. Keywords: cell type comparison, stress response
2008-03-21 | GSE10905 | GEO
Project description:Only about 25% of familial breast cancer is explained by mutations in BRCA1 and BRCA2, fewer by moderate penetrance genes like P53, PTEN, CHEK2, ATM and PALB2 and an unknown fraction by common variants of genes with low penetrance. Evidence suggests that additional dominant breast cancer genes exist and these are referred to as BRCAX. Clinical presentation of families with highly increased incidence of breast cancer that are non-BRCA1/BRCA2, suggests dominant inheritance of such high penetrance breast cancer genes. Because cancer genes often confer a specific clinical presentation (e.g. age of onset, sex-ratio, tissue spectrum) it seems useful to initiate their discovery by such clinical criteria. An earlier linkage study of BRCAX / non-BRCA1/2 breast cancer families aimed to enrich for a common genetic defect by setting stringent inclusion criteria, failed to identify new breast cancer susceptibility loci. Motivated by results of BRCA1 and BRCA2 breast tumors that have characteristic genomic signatures (array-CGH 'phenotypes'), we present the largest dataset to date showing the genomic profiles of 58 BRCAX primary breast tumors by array-CGH and show by unsupervised hierarchical clustering that they form a heterogeneous group with 4 distinct subtypes that are different from (n = 48) sporadic controls. This provides a possible explanation for the lack of high LOD scores in linkage studies. The presence of more than one BRCAX sub-type suggests the existence of more than one BRCAX gene. We propose approaches that can be employed to stratify BRCAX families based on array-CGH data.
2011-02-01 | GSE18626 | GEO
Project description:We analysed a cohort of 75 BRCA1, BRCA2 and non-BRCA1/2 breast tumors by gene expression profiling and found that 74% BRCA1 tumors were basal-like, 73% of BRCA2 tumors were luminal A or B, and 52% non-BRCA1/2 tumors were luminal A. Thirty-four tumors were also analysed by single nucleotide polymorphism-comparative genomic hybridization (SNP-CGH) arrays. Copy number data could predict whether a tumor was basal-like or luminal with high accuracy, but could not predict its mutation class. Basal-like BRCA1 and basal-like non-BRCA1 tumors were very similar, and contained the highest number of chromosome aberrations. We identified regions of frequent gain containing potential driver genes in the basal (8q and 12p) and luminal A tumors (1q and 17q). Regions of homozygous loss associated with decreased expression of potential tumor suppressor genes were also detected, including in basal tumors (5q and 9p), and basal and luminal tumors (10q). This study highlights the heterogeneity of familial tumors and the clinical consequences for treatment and prognosis.
2009-12-16 | GSE19177 | GEO
Project description:Amplification of chromosomal region 11q13, containing the cell cycle regulatory gene CCND1, is frequently found in breast cancer and other malignancies. It is associated with the favourable oestrogen receptor (ER) positive breast tumour phenotype, but also with poor prognosis and treatment failure. 11q13 spans almost 14 Mb and contains more than 200 genes and is affected by various patterns of copy number gains, suggesting complex mechanisms and selective pressure during tumour progression. In the present study we used 32k tiling BAC array CGH to analyse 94 CCND1-amplified breast tumours from sporadic, hereditary and familial breast cancers to fine map chromosome 11q13. A set containing 281 CCND1-non-amplified breast tumours was used for comparisons. We used gene expression data to further validate the functional effect of gene amplification. We identified six core regions covering 11q13.1-q14.1 that were amplified in different combinations. The major core contained CCND1, whereas two cores were found proximal of CCND1 and three distal. The majority of the CCND1-amplified tumours were ER-positive and classified as luminal B. Furthermore, we found that CCND1 amplification is associated with a more aggressive phenotype within histological grade 2 tumours and luminal A subtype tumours. Amplification was equally prevalent in familial and sporadic tumours, but strikingly rare in BRCA1- and BRCA2- mutated tumours. We conclude that 11q13 includes many potential target genes in addition to CCND1. Genomic profiling of 94 CCND1-amplified breast tumors using tiling BAC aCGH. A number of cases were hybridized as replicates or replicate as dye-swaps.
2011-11-23 | E-GEOD-32578 | biostudies-arrayexpress