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Gene Expression in Normal and Tumor Ovarian Epithelial Cells from Non-carriers and Heterozygous Carriers of a BRCA French Canadian Mutation.

ABSTRACT: We hypothesized that the transcriptome of primary cultures of morphologically normal ovarian surface epithelial cells could be altered by the presence of a heterozygous BRCA1 or BRCA2 mutation. We aimed to discover early events associated to ovarian carcinogenesis, which could represent putative targets for preventive strategies of this silent killer tumor. We identified the first molecular signature associated with French Canadian BRCA1 or BRCA2 founder mutations in morphologically normal ovarian epithelial cells. We discovered that wild-type and mutated BRCA2 allelic transcripts were expressed not only in morphologically normal but also in tumor cells from 8765delAG BRCA2 carriers. Further analysis of morphologically normal ovarian and tumor cells from C4446T BRCA1 carriers lead to the same observation. Our data support the idea that one single hit in BRCA1 or BRCA2 is sufficient to alter the transcriptome of phenotypically normal ovarian epithelial cell. The highest level of BRCA2 mutated allele transcript expression was measured in cells originating from the most aggressive ovarian tumor. The penetrance of the mutation and the aggressiveness of the related tumor could depend on a dosage effect of the mutated allele transcript.

ORGANISM(S): Homo sapiens

PROVIDER: GSE34928 | GEO | 2012/06/15

SECONDARY ACCESSION(S): PRJNA150995

REPOSITORIES: GEO

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Gene Expression in Normal and Tumor Ovarian Epithelial Cells from Non-carriers and Heterozygous Carriers of a BRCA French Canadian Mutation.

Project description:We hypothesized that the transcriptome of primary cultures of morphologically normal ovarian surface epithelial cells could be altered by the presence of a heterozygous BRCA1 or BRCA2 mutation. We aimed to discover early events associated to ovarian carcinogenesis, which could represent putative targets for preventive strategies of this silent killer tumor. We identified the first molecular signature associated with French Canadian BRCA1 or BRCA2 founder mutations in morphologically normal ovarian epithelial cells. We discovered that wild-type and mutated BRCA2 allelic transcripts were expressed not only in morphologically normal but also in tumor cells from 8765delAG BRCA2 carriers. Further analysis of morphologically normal ovarian and tumor cells from C4446T BRCA1 carriers lead to the same observation. Our data support the idea that one single hit in BRCA1 or BRCA2 is sufficient to alter the transcriptome of phenotypically normal ovarian epithelial cell. The highest level of BRCA2 mutated allele transcript expression was measured in cells originating from the most aggressive ovarian tumor. The penetrance of the mutation and the aggressiveness of the related tumor could depend on a dosage effect of the mutated allele transcript. We studied the molecular profiles associated with 5 a priori classes of samples : 4 non-familial morphologically normal ovarian surface epithelium (NOSEs) : NM class, 2 BRCA1-mutated NOSEs : M1 class, 3 BRCA2-mutated NOSEs : M2 class, 3 BRCA1-mutated ovarian tumor cells (TOVs) : TM1 class and one BRCA2-mutated TOV :TM2 class. No technical replicates were included in this study. The following contrasts were computed : NM vs. M1, NM vs. M2, M1 vs. M2, M1 vs. TM1 and M (M1 union M2) vs. TM (TM1 union TM2).

2012-06-14 | E-GEOD-34928 | biostudies-arrayexpress

Normal human mammary tissues from BRCA1 mutation carriers, non-BRCA1/2 mutation carriers and normal women

2009-08-01 | GSE17072 | GEO

Altered gene expression in normal breast and ovarian epithelial cells from BRCA1 and BRCA2 mutation carriers

Project description:Early genetic changes during cancer initiation may provide targets for agents that delay, or even prevent, cancer. We hypothesized that cells bearing a single inherited âhitâ in a tumor suppressor gene express an altered mRNA repertoire that may identify targets for measures that could delay or even prevent progression to carcinoma. Here, we report on the transcriptomes of primary breast and ovarian epithelial cells cultured from BRCA1 and BRCA2 mutation-carriers and controls. Our comparison analyses identified multiple changes in gene expression, in both tissues for both mutations that were independently validated by real-time RT-PCR analysis. Several of the differentially expressed genes had been previously proposed as cancer markers including, mammaglobin in breast cancer and serum amyloid in ovarian cancer. These findings demonstrate that heterozygosity for a mutant tumor suppressor gene can alter the expression profiles of phenotypically normal epithelial cells in a gene-specific manner, and that these detectable effects of âone-hitâ represent early molecular changes in tumorigenesis that may serve as novel biomarkers of cancer risk and as targets for chemoprevention Using affymetrix U133 plus2 chips, we compare the transcriptome of primary breast and ovarian epithelial cultures derived from subjects predisposed to cancer, bearing monoallelic BRCA1 or BRCA2 mutations, with corresponding cultures from control individuals that do not have mutations. For both breast and ovarian samples, epithelial cell cultures were generated from 6 subjects that have both BRCA1 or BRCA2 mutations and 6 subjects that do not have mutations. Affymetrix U133 plus 2 chips were used to profile the transcriptome of BRCA1 or BRCA2 mutant and wild type. In total 36 chips were used to profile 18 samples from both breast and ovary, 6 mutant (BRCA1 and BRCA2) and 6 wild type.

2010-03-07 | E-GEOD-19383 | biostudies-arrayexpress

Normal human mammary tissues from BRCA1 mutation carriers, non-BRCA1/2 mutation carriers and normal women

Project description:Gene expression profiles of normal human mammary tissue from BRCA1 mutation carriers, non-BRCA1/2 mutation carriers and normal women. RNA was prepared from normal breast tissue (confirmed by pathology) from reduction mammoplasties (n=5) and prophylactic mastectomies of known BRCA1 (n=7) and non-BRCA1/2 mutation carriers (n=8). non-BRCA1/2 carriers were individuals with a strong family history of breast cancer (kConFab Category 1 (http://www.kconfab.org/Collection/Eligibility.shtml) where no mutation in BRCA1 or BRCA2 has been identified in the family by high sensitivity testing (http://www.kconfab.org/Progress/Sensitivity.shtml) of any individual affected by breast or ovarian cancer. Normal breast samples refer to reduction mammoplasty specimens, where family history is generally not known. Microarray expression profiles were obtained from whole pre-neoplastic breast tissue from three categories of patient, as described in the summary. Samples were checked for keratin gene expression levels as a marker for epithelium tissue, and a number of samples were removed because two or more keratin genes lacked detectable expression (BeadStudio detection p-value 0.01). One other sample was removed because its expression profile appeared abnormal. Out of 36 samples initially profiled, 20 passed the quality filters and were used for the final analysis.

2009-08-01 | E-GEOD-17072 | biostudies-arrayexpress

Spatial Transcriptomics Suggests That Alterations 4 Occur in the Preneoplastic Breast Microenvironment of 5 Q2 BRCA1/2 Mutation Carriers

Project description:Breast cancer is the most common cancer in females, affecting one in every eight women and accounting for the majority of cancer-related deaths in women worldwide. Germline mutations in the BRCA1 and BRCA2 genes are significant risk factors for specific subtypes of breast cancer. BRCA1 mutations are associated with basal-like breast cancers, whereas BRCA2 mutations are associated with luminal-like disease. Defects in mammary epithelial cell differentiation have been previously recognized in germline BRCA1/2 mutation carriers even before cancer incidence. However, the underlying mechanism is largely unknown. Here, we employ spatial transcriptomics to investigate defects in mammary epithelial cell differentiation accompanied by distinct microenvironmental alterations in preneoplastic breast tissues from BRCA1/2 mutation carriers and normal breast tissues from non-carrier controls. We uncovered spatially defined receptor-ligand interactions in these tissues for the investigation of autocrine and paracrine signaling. We discovered that β1-integrin-mediated autocrine signaling in BRCA2-deficient mammary epithelial cells may differ from BRCA1-deficient mammary epithelial cells. In addition, we found that the epithelial-to-stromal paracrine signaling in the breast tissues of BRCA1/2 mutation carriers is greater than in control tissues. More integrin-ligand pairs were differentially correlated in BRCA1/2-mutant breast tissues than non-carrier breast tissues with more integrin receptor-expressing stromal cells. Implications: These results suggest alterations in the communication between mammary epithelial cells and the microenvironment in BRCA1 and BRCA2 mutation carriers, laying the foundation for designing innovative breast cancer chemo-prevention strategies for high-risk patients.

2023-10-11 | GSE234017 | GEO

Altered gene expression in normal breast and ovarian epithelial cells from BRCA1 and BRCA2 mutation carriers

Project description:Early genetic changes during cancer initiation may provide targets for agents that delay, or even prevent, cancer. We hypothesized that cells bearing a single inherited “hit” in a tumor suppressor gene express an altered mRNA repertoire that may identify targets for measures that could delay or even prevent progression to carcinoma. Here, we report on the transcriptomes of primary breast and ovarian epithelial cells cultured from BRCA1 and BRCA2 mutation-carriers and controls. Our comparison analyses identified multiple changes in gene expression, in both tissues for both mutations that were independently validated by real-time RT-PCR analysis. Several of the differentially expressed genes had been previously proposed as cancer markers including, mammaglobin in breast cancer and serum amyloid in ovarian cancer. These findings demonstrate that heterozygosity for a mutant tumor suppressor gene can alter the expression profiles of phenotypically normal epithelial cells in a gene-specific manner, and that these detectable effects of “one-hit” represent early molecular changes in tumorigenesis that may serve as novel biomarkers of cancer risk and as targets for chemoprevention Using affymetrix U133 plus2 chips, we compare the transcriptome of primary breast and ovarian epithelial cultures derived from subjects predisposed to cancer, bearing monoallelic BRCA1 or BRCA2 mutations, with corresponding cultures from control individuals that do not have mutations.

2010-03-01 | GSE19383 | GEO

BRCA1 and BRCA2 classification of ovarian cancer

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

Myoepithelial cell perturbations in BRCA mutation carriers and in DCIS (ductal carcinoma in situ)

Project description:We describe the gene expression profiles and enhancer landscape of normal myoepithelial cells and perturbations of these in BRCA1 and BRCA2 mutation carriers and in DCIS. We identified a myoepithelial transcription regulatory network orchestrated by p63 and TCF7 and defined the genomic targets of these transcription factors by ChIP-seq. While the majority of myoepithelial cells co-express p63 and TCF7 in normal breast of healthy women, the frequency of these cells is significantly lower in BRCA1 mutation carriers and in DCIS. Downregulation of p63 in MCF10DCIS cells leads to loss of myoepithelial cells and invasive tumors, whereas overexpression of TCF7 enhances tumor growth. Our findings suggest that loss of normal myoepithelial cell function facilitates in situ to invasive carcinoma transition and it may also enhance tumor initiation in BRCA mutation carriers.

2019-08-20 | GSE113909 | GEO

Myoepithelial cell perturbations in BRCA mutation carriers and in DCIS (ductal carcinoma in situ)

2021-04-27 | GSE113795 | GEO

Expression data from mammary epithelial cells from BRCA1 mutation carriers and non BRCA1 mutation carriers

Project description:Female BRCA1 mutation carriers have a nearly 80% probability of developing breast cancer during their life-time. We hypothesized that the breast epithelium at risk in BRCA1 mutation carriers harbors mammary epithelial cells (MECs) with altered proliferation and differentiation properties. Microarray studies revealed that PMEC colonies from BRCA1 mutation carriers anticipate expression profiles found in BRCA1-related tumors, and that the EGFR pathway is upregulated in BRCA1 mutation carriers compared ton non BRCA1 mutation carriers. Keywords: Class comparison and pathway analysis 10 colonies were collected and RNA was isolated using the Absolutely RNA Nanoprep kit, Stratagene. The arrays included duplicates from four normal controls and from two BRCA1 mutation carriers and single arrays from another two BRCA1 mutation carriers.

2008-11-19 | E-GEOD-13671 | biostudies-arrayexpress

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