Homo sapiens
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PROVIDER: PRJNA118311 | ENA |
REPOSITORIES: ENA
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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:We have analyzed, using DNA microarrays, putative differences in gene-expression level between hereditary BRCA1 mutation-linked and sporadic breast cancer. Our results show that a previously reported marked difference between BRCA1-mutation linked and sporadic breast cancer was probably due to uneven stratification of samples with different ER status and basal-like versus luminal-like subtype. We observed that apparent difference between BRCA1-linked and other types of breast cancer found in univariate analysis was diminished when data were corrected for ER status and molecular subtype in multivariate analyses. In fact, the difference in gene expression pattern of BRCA1-mutated and sporadic cancer is very discrete. These conclusions were supported by the results of Q-PCR validation. We also found that BRCA1 gene inactivation due to promoter hypermethylation had similar effect on general gene expression profile as mutation-induced protein truncation. This suggests that in the molecular studies of hereditary breast cancer, BRCA1 gene methylation should be recognized and considered together with gene mutation. We analyzed 35 breast cancer specimens. Surgical samples obtained during mastectomy were flash-frozen in liquid nitrogen and stored at -80°C. Only samples from patients without neoadjuvant chemotherapy were used in this study as chemotherapy may seriously affect gene expression profile. All tissue samples were collected at the Pomeranian Medical University in Szczecin. Seventeen tumor samples were collected from patients with hereditary breast cancer: 12 were derived from tumors affecting women with hereditary BRCA1 mutation, the only one from a woman with BRCA2 mutation, while another eight cases had familial history of breast/ovarian cancer, but were negative for the BRCA1/2 mutations (so called BRCAx cases). Proportion of BRCA1 and BRCA2 mutated tumors was typical for the Polish population. Ten samples were derived from patients with apparently sporadic disease (no familial history of cancer) while 4 patients had a history of familial cancer aggregation (FCA) but without prevalence of breast/ovarian cancers. Thus, these samples were merged with sporadic samples in most of the analyses. All BRCA1 mutation-linked tumors in our study were negative for estrogen receptor (by immunohistochemistry, standard procedures for ER, PGR and HER2 staining were applied), while the only BRCA2-mutated tumor was ER-positive. There were 26 ductal and 5 medullary carcinomas within the study group, which is consistent with the distribution of histopathological types in BRCA1 mutation carriers. Patients were diagnosed at stage T1-2, N0-1 and M0. Caution: this submission contains the data from 6 microarrays done on the normal/pathologically unchanged breast tissue from breast cancer patiets. The data from normal tissues was not analyzed in the paper BRCA1-related gene signature in breast cancer is strongly influenced by ER status and molecular type by Lisowska et al., 2011, Front Biosci (Elite Ed). 2011 Jan 1;3:125-36
2013-09-05 | E-GEOD-50567 | biostudies-arrayexpress
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: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:Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants of unclear pathogen significance are found in the families, constituting an increasing clinical challenge. New methods are therefore needed to improve the detection rate and aid the interpretation of the clinically uncertain variants. In this study we analyzed a series of 33 BRCA1, 22 BRCA2, and 128 sporadic tumors by RNA profiling to investigate the classification potential of RNA profiles to predict BRCA1/2 mutation status. We found that breast tumors from BRCA1 and BRCA2 mutation carriers display characteristic RNA expression patterns, allowing them to be distinguished from sporadic tumors. The majority of BRCA1 tumors were basal-like while BRCA2 tumors were mainly luminal B. Using RNA profiles, we were able to distinguish BRCA1 tumors from sporadic tumors among basal-like tumors with 83% accuracy and BRCA2 from sporadic tumors among luminal B tumors with 89% accuracy. Furthermore, subtype-specific BRCA1/2 gene signatures were successfully validated in two independent data sets with high accuracies. Although additional validation studies are required, indication of BRCA1/2 involvement (“BRCAness”) by RNA profiling could potentially be valuable as a tool for distinguishing pathogenic mutations from benign variants, for identification of undetected mutation carriers, and for selecting patients sensitive to new therapeutics such as PARP inhibitors. Gene expression profiling of 183 breast tumor samples. Breast tumors from hereditary breast cancer patients carrying a pathogenic BRCA1 (n=33) or BRCA2 (n=22) germ-line mutation were included in the study. Serving as a representative control group, primary breast tumor samples (n=128) were randomly selected. The study was conducted using Agilent-029949 Custom SurePrint G3 Human GE 8x60K Microarray platform. For cross-platform validation, a subset of the tumor samples (92 of the 183 samples) were analyzed by our in-house spotted microarray platform.
2013-06-28 | E-GEOD-40115 | biostudies-arrayexpress
Project description:Inactivating germline BRCA1 and BRCA2 mutations confer a defect in homologous recombination DNA repair which was found to leave traces in tumor DNA copy number aberration (CNA) profiles. In analogy to previously trained breast cancer CNA classifiers that predicted association with BRCA1 and BRCA2 mutated cancer and benefit of high dose double strand break inducing chemotherapy, we trained BRCA1 and BRCA2 classifiers on CNA profiles of 50 BRCA1 mutated, 10 BRCA2 mutated and 13 non-familial ovarian cancers and investigated whether tumor type and mutation type independent classifiers could be trained. The cross validated area under the curve of the receiver/operator characteristic curve of ovarian cancer BRCA1 and BRCA2 classifiers were 0.67 (95% CI: 0.55-0.78) and 0.91 (95% CI: 0.79-1). These classifiers identified the majority of the samples with germline and somatic BRCA1 and BRCA2 mutations and BRCA1 promoter hypermethylation in the Cancer Genome Atlas (TCGA) dataset. Combining tumor type or mutated gene did not yield higher AUCs than single gene classifiers, although the ovarian BRCA1+BRCA2 classifier identified most BRCA1 and -2 mutated cases, including those in the TCGA dataset, and a combined breast and ovarian cancer BRCA1 classifier may improve response prediction to double strand break inducing chemotherapy.
2021-12-31 | GSE111688 | GEO
Project description:It is now well understood that epigenetic alterations occur frequently in sporadic breast carcinogenesis, but little is known about the epigenetic alterations associated with familial breast tumors. We performed genome-wide DNA methylation profiling on familial breast cancers (n=33) to identify patterns of methylation specific to the different mutation groups (BRCA1, BRCA2 and BRCAx) or intrinsic subtypes of breast cancer (basal, luminal A, luminal B, HER2 and normal-like). We used methylated DNA immunoprecipitation (meDIP) on Affymetrix human promoter chips to interrogate methylation profiles across 25,500 distinct transcripts.
2010-03-12 | GSE17125 | GEO
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:Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we utilized gene expression profiling to molecularly subtype 577 breast tumors, including 73 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1 locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated and 48 non-BRCA1/2-mutated breast tumors using a custom-designed high-density oligomicroarray covering the RB1 gene. We found a strong association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2-mutated breast tumors. RB1 was identified as a major target for genomic disruption in tumors arising in BRCA1 mutation carriers and in sporadic tumors with BRCA1 promoter-methylation, but rarely in other breast cancers. Homozygous deletions, intragenic breaks, or microdeletions were found in 33% of BRCA1-mutant tumors, 36% of BRCA1 promoter-methylated basal-like tumors, 13% of non-BRCA1 deficient basal-like tumors, and 3% of BRCA2-mutated tumors. In addition, RB1 was frequently inactivated by gross gene disruption in BRCA1-related hereditary breast cancer and BRCA1-methylated sporadic basal-like breast cancer, but rarely in BRCA2-hereditary breast cancer and non-BRCA1-deficient sporadic breast cancers. Together, our findings demonstrate the existence of genetic heterogeneity within the basal-like breast cancer subtype that is based upon BRCA1-status. Gene expression profiling of breast tumors. Dual color common reference gene expression study using 55K oligonucleotide microarrays.
2012-06-26 | E-GEOD-25307 | biostudies-arrayexpress
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