Two pathogenic germline truncating variants of BRCA2 confer different haploinsufficiency phenotypes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1136477 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR29847452_1.fastq.gz | Fastqsanger.gz | |||
| SRR29847452_2.fastq.gz | Fastqsanger.gz | |||
| SRR29847455_1.fastq.gz | Fastqsanger.gz | |||
| SRR29847455_2.fastq.gz | Fastqsanger.gz |
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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: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
Project description:Individuals with a single functional copy of the BRCA2 tumor suppressor have elevated risks for breast, ovarian, and other solid tumor malignancies. The exact mechanisms of carcinogenesis due to BRCA2 haploinsufficiency remain unclear, but one possibility is that at-risk cells are subject to acute periods of decreased BRCA2 availability and function ("BRCA2-crisis"), which may contribute to disease. Here, we establish an in vitro model for BRCA2-crisis that demonstrates chromatin remodeling and activation of an NF-κB survival pathway in response to transient BRCA2 depletion. Mechanistically, we identify BRCA2 chromatin binding, histone acetylation, and associated transcriptional activity as critical determinants of the epigenetic response to BRCA2-crisis. These chromatin alterations are reflected in transcriptional profiles of pre-malignant tissues from BRCA2 carriers and, therefore, may reflect natural steps in human disease. By modeling BRCA2-crisis in vitro, we have derived insights into pre-neoplastic molecular alterations that may enhance the development of preventative therapies.
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Project description:Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.
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Project description:There has been interest in the literature in the possible existence of a gene that predisposes to both breast cancer (BC) and colorectal cancer (CRC). We describe the detailed characterisation of one kindred, MON1080, with 10 cases of BC or CRC invasive cancer among 26 first-, second- or third-degree relatives. Linkage analysis suggested that a mutation was present in BRCA2. DNA sequencing from III: 22 (diagnosed with lobular BC) identified a BRCA2 exon 3 542G>T (L105X) mutation. Her sister (III: 25) had BC and endometrial cancer and carries the same mutation. Following immunohistochemical and microsatellite instability studies, mutation analysis by protein truncation test, cDNA sequencing and quantitative real-time PCR revealed a deletion of MSH2 exon 8 in III: 25, confirming her as a double heterozygote for truncating mutations in both BRCA2 and MSH2. The exon 8 deletion was identified as a 14.9 kb deletion occurring between two Alu sequences. The breakpoint lies within a sequence of 45 bp that is identical in both Alu sequences. In this large BC/CRC kindred, MON1080, disease-causing truncating mutations are present in both MSH2 and BRCA2. There appeared to be no increased susceptibility to the development of colorectal tumours in BRCA2 mutation carriers or to the development of breast tumours in MSH2 mutation carriers. Additionally, two double heterozygotes did not appear to have a different phenotype than would be expected from the presence of a mutation in each gene alone.
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Project description:We report differential effects of mutations in genes of the homologous recombination (HR) pathway on response after ICB administration in mouse and human tumors, and show that truncating mutations in BRCA2 are associated with superior response to ICB compared to BRCA1-deficient tumors. Immunogenomic analyses demonstrated that mutations in BRCA1 and BRCA2 differentially modulate the tumor-immune microenvironment, with gene expression programs related to both adaptive and innate immune pathways enriched in BRCA2-deficient tumors. Single-cell RNA sequencing further revealed distinct T cell, NK, macrophage, and dendritic cell populations enriched in BRCA2 mutant tumors relative to BRCA1-deficient tumors.
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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:Breast cancer gene 2 (BRCA2) deleterious mutations confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition due to its critical role in DNA repair. PARP inhibitor Olaparib is now approved and several other PARP inhibitors are now in different stages of clinical trials. Development of resistance to PARP inhibitors limits their clinical utility. The mechanism of resistance remains not fully understood. Here we show that amplification of mutant BRCA2 confers PARP inhibitor resistance. The amplification of mutant BRCA2 gene copies correlates with an increase in mutant BRCA2 expression and an increase in the levels of its interacting proteins PALB2 and RAD51. In addition, homologous recombination mediated DNA repair is rescued in these cells as evidenced by the formation of RAD51 focus formation. The overexpressed mutant BRCA2 is essential for the observed PARP inhibitor resistance because knockdown of its expression is sufficient to re-sensitize these cells to PARP inhibition. Collectively, our results indicate a new mechanism of resistance to PARP inhibitor in BRCA2 mutant cancer cells
2017-09-02 | GSE86394 | GEO
Project description:Individuals with a single functional copy of the BRCA2 tumor suppressor have elevated risks for breast, ovarian and other solid tumor malignancies. The exact mechanisms of carcinogenesis due to BRCA2 haploinsufficiency remain unclear, but one possibility is that at-risk cells are subject to acute periods of decreased BRCA2 availability and function (“BRCA2-crisis”), which may contribute to disease. Here we establish an in vitro model for BRCA2-crisis that demonstrates novel epigenetic remodeling and activation of an NF-κB survival pathway in response to transient BRCA2-depletion. Mechanistically, we identify BRCA2 chromatin binding, histone acetylation and associated transcriptional activity as critical determinants of the epigenetic response to BRCA2-crisis. These epigenetic alterations are reflected in transcriptional profiles of pre-malignant tissues from BRCA2-carriers and therefore may reflect natural steps in human disease. By modeling BRCA2-crisis in vitro we have derived insights into pre-neoplastic molecular alterations that may enhance the development of preventative therapies.
2019-08-07 | GSE133728 | GEO
Project description:We describe an 8 year old child who had disseminated anaplastic medulloblastoma and a deleterious heterozygous BRCA2 6174delT germline mutation. Molecular profiling was consistent with Group 4 medulloblastoma. The posterior fossa mass was resected and the patient received intensive chemotherapy and craniospinal irradiation. Despite this, the patient succumbed to a second recurrence of his medulloblastoma, which presented eight months after diagnosis as malignant pleural and peritoneal effusions. Continuous medulloblastoma cell lines were isolated from the original tumor (CHLA-01-MED) and the malignant pleural effusion (CHLA-01R-MED). Here we provide their analyses, including in vitro and in vivo growth, drug sensitivity, comparative genomic hybridization and next generation sequencing analysis. In addition to the BRCA2 6174delT, the medulloblastoma cells had amplification of MYC, deletion at Xp11.2 and isochromosome 17, but no structural variations or overexpression of GFI1 or GFI1B. To our knowledge, this is the first pair of diagnosis/recurrence medulloblastoma cell lines, the only medulloblastoma cell lines with BRCA2 6174delT described to date, and the first reported case of a child with medulloblastoma associated with a germline BRCA2 6174delT who did not also have Fanconi anemia. Continuous medulloblastoma cell lines were isolated from the original tumor (CHLA-01-MED) and the malignant pleural effusion (CHLA-01R-MED). Here we provide their analyses, including in vitro and in vivo growth, drug sensitivity, comparative genomic hybridization with Agilent 400k CGH arrays and whole transcriptome RNASeq analysis.
2015-07-06 | E-GEOD-70003 | biostudies-arrayexpress