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Identification of BRCA1/2 mutation carriers using circulating microRNA profiles

ABSTRACT: Identifying germline BRCA1/2 mutation carriers is vital for reducing their risk of breast and ovarian cancer; however, many carriers are not referred for genetic testing. While population-wide testing is not feasible, a cheap functional screen for phenotypic ‘BRCAness’ could guide efforts for focused genetic counseling and improve cancer prevention and early detection. The aim of this study was to derive a serum-based miRNA panel to identify BRCA1/2 mutation carriers among healthy controls. We performed a diagnostic biomarker study based on serum samples collected between by six international cohorts. Serum samples from 653 healthy women with known mutation status of BRCA1 and BRCA2 were used in the analysis. All individuals had no history of prior cancer or any detected malignancies for at least 12 months after sample collection. Among the study population, 350 (53.6%) subjects had BRCA mutations and 303 (46.4%) were BRCA1/2 – wild-type. In all individuals, we isolated and quantified miRNAs expression using RNA-sequencing. Variable selection based on differential expression analysis on merged, batch adjusted cohorts was performed to identify a set of miRNAs associated with BRCA mutation carrier status.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226445 | GEO | 2023/05/02

REPOSITORIES: GEO

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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

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Identification of BRCA1/2 mutation carriers using circulating microRNA profiles

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