Mutations in homologous recombination genes BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE137818 | GEO | 2020/08/27
REPOSITORIES: GEO
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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: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.
2013-06-28 | GSE40115 | GEO
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
2008-09-30 | GSE9483 | GEO
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:Differentially expressed genes between BRCA1/BRCA2 negative and positive mutation driven-tumors. Screening for germline mutations was performed in a cohort of 55 patients under the age of 35 years in the BRCA1, BRCA2, CHEK2 (c.del1,100C) and TP53 genes, and the respective tumors were investigated regarding hormonal receptors status, HER2 expression. Transcriptional profiles were performed using Agilent one color hybridizations in a G4112F platform.
2013-04-09 | E-GEOD-37126 | biostudies-arrayexpress
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:Inactivating germline monoallelic mutations in the tumor suppressor BRCA2 predispose to breast and ovarian cancer. BRCA2 is essential in DNA repair via homologous recombination (HR). Tumorigenesis in this setting is thought to require the inactivation of the second allele; however, this event is not always observed suggesting haploinsufficiency. We investigated this question recreating two BRCA2 pathogenic truncating variants in heterozygosis in breast epithelial cells. One prompted sensitivity to PARP inhibitors (PARPi) and reduced HR capacity unlike the other. The other resulted in transcriptomic and epigenetic changes including histone H4 acetylation levels and NF-kB activation that we link to PCAF acetyl transferase. These changes impacted on cell migration and proliferation in 2D and 3D, processes that were also deregulated in tumors. Our work demonstrates that distinct truncating variants of BRCA2 are not phenotypically equivalent. It also identifies PCAF as shaping BRCA2-related gene expression. These findings may have implications in cancer prevention.
2024-11-21 | GSE272335 | GEO
Project description:We used complementary DNA (cDNA) microarrays to compare gene expression patterns in ovarian cancers associated with BRCA1 or BRCA2 mutations with gene expression patterns in sporadic epithelial ovarian cancers and to identify patterns common to both hereditary and sporadic tumors.
2016-05-28 | GSE82007 | GEO
Project description:Approximately 5% of all breast cancers can be attributed to an inherited mutation in one of two cancer susceptibility genes, BRCA1 and BRCA2. We searched for genes that have the potential to distinguish healthy BRCA1 and BRCA2 mutation carriers from non-carriers based on differences in expression profiling. Using expression microarrays we compared gene expression of irradiated lymphocytes from BRCA1 and BRCA2 mutation carriers versus control non-carriers. We identified 137 probe sets in BRCA1 carriers and 1345 in BRCA2 carriers with differential gene expression. Gene Ontology analysis revealed that most of these genes relate to regulation pathways of DNA repair processes, cell cycle regulation and apoptosis. Real-time PCR was performed on the 36 genes which were most prominently differentially expressed in the microarray assay; 21 genes were shown to be significantly differentially expressed in BRCA1 or BRCA2 mutation carriers as compared to controls (p<0.05). Based on a validation study with 40 mutation carriers and 17 non-carriers, a multiplex model that included six or more coincidental genes of 18 selected genes was constructed in order to predict the risk of carrying a mutation. The results using this model showed sensitivity 95% and specificity 88%. In summary, our study provides insight into the biological effect of heterozygous mutations in BRCA1 and BRCA2 genes in response to ionizing irradiation induced DNA damage. We also suggest a set of 18 genes that can be used as a prediction and screening tool for BRCA1 or BRCA2 mutational carriers by using easily obtained lymphocytes. Using expression microarrays we compared gene expression of irradiated lymphocytes from BRCA1 and BRCA2 mutation carriers versus control non-carriers Fresh blood samples were obtained from 9 BRCA1 and 8 BRCA2 mutation carriers and 9 mutation-negative women. Lymphocytes were collected from fresh blood samples, and RNA was extracted one hour after γ-irradiation
2013-01-10 | E-GEOD-39976 | biostudies-arrayexpress
Project description:Abnormalities provoked in human cells heterozygous for clinically relevant truncating mutations in BRCA2 by their exposure to naturally occurring aldehydes define a mechanism promoting carcinogenesis in mutation carriers. The ubiquitous metabolite and environmental toxin, formaldehyde, triggers replication fork instability and structural chromosomal aberrations in BRCA2 heterozygous cells. These abnormalities arise from a previously unrecognized effect of formaldehyde to selectively induce the proteasomal degradation of BRCA2, inducing functional haploinsufficiency only in cells where BRCA2 expression is already compromised by a heterozygous mutation. Similar effects are observed with acetaldehyde, a toxic product of alcohol catabolism. Replication fork instability and chromosomal aberrations in aldehyde-exposed cells arise from the unscheduled accumulation of RNA-DNA hybrids, revealing a mechanism driving genomic instability in BRCA2 heterozygous cells. We propose a model for cancer pathogenesis in which aldehyde exposure unmasks the carcinogenic potential of heterozygous BRCA2 mutations, with public health implications in mutation carriers.
2017-06-02 | PXD006106 | Pride