Dataset Information

BRCA mutations in the manifestation and treatment of ovarian cancer.

ABSTRACT: BRCA genes are important for the integrity and stability of genetic material and play key roles in repairing DNA breaks via high fidelity homologous recombination. BRCA mutations are known to predispose carriers to gynecological malignancies, accounting for a majority of hereditary OC cases. Known to be lethal, OC is difficult to detect and control. Testing for BRCA mutations is a key step in the risk assessment, prognosis, treatment and prevention of OC and current clinical guidelines recommend BRCA mutation testing for all OCs of epithelial origin. Studies have established that ovarian tumors harboring BRCA mutations have distinct molecular and histo-pathological features that can be exploited for effective, targeted treatment. Deficiencies in DNA repair pathways that arise as a result of BRCA mutations make them hypersensitive to DNA-damaging treatments such as platinum chemotherapy and PARP inhibitors. Different combinations of treatment regimens which have the potential to greatly improve prognosis and disease outcomes are currently being evaluated. However, the issue of developing resistance to these treatments remains unresolved. This review emphasizes unique features of BRCA mutated OC and outlines the lay of the land in terms of diagnosis and treatment, while aiming to unravel the challenges that are part of its management.

SUBMITTER: Pan Z

PROVIDER: S-EPMC5722593 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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BRCA mutations in the manifestation and treatment of ovarian cancer.

Pan Zimin Z Xie Xing X

Oncotarget 20170530 57

BRCA genes are important for the integrity and stability of genetic material and play key roles in repairing DNA breaks via high fidelity homologous recombination. BRCA mutations are known to predispose carriers to gynecological malignancies, accounting for a majority of hereditary OC cases. Known to be lethal, OC is difficult to detect and control. Testing for BRCA mutations is a key step in the risk assessment, prognosis, treatment and prevention of OC and current clinical ...[more]

PMID: 29228641

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Project description:Ovarian cancer, a complex and aggressive malignancy, remains a significant challenge in clinical oncology due to its heterogeneous nature and limited therapeutic options. In this study, across Pakistani ovarian cancer patients, we conducted a comprehensive analysis of mutations within the BRCA1 and BRCA2 genes to elucidate their potential implications in ovarian cancer susceptibility and progression. Employing Next-Generation Sequencing (NGS), we conducted a comprehensive mutational analysis of BRCA1/2 genes. Kaplan Meier analysis was used to analyze the effect of pathogenic mutations on the survival outcomes of ovarian cancer patients. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Immunohistochemistry (IHC) analyses were conducted to analyze the downstream effect of the pathogenic mutations. Targeted bisulfite sequencing (bisulfite-seq) analysis facilitated the investigation of epigenetic contributions to gene expression regulation. Enrichment analysis was conducted to uncover significant Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with BRCA1/2. Exploring DrugBank, we identified potential drugs capable of modulating BRCA1/2 expression regulation. NGS analysis identified three clinically significant pathogenic mutations within the BRCA1 gene and two within the BRCA2 gene, shedding light on their potential involvement in ovarian cancer susceptibility and progression. Kaplan Meier analysis unveiled poor overall survival (OS) associated with the identified pathogenic mutations, accentuating their prognostic value. Expression analysis using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and IHC demonstrated a significant up-regulation of BRCA1 and BRCA2 genes in ovarian cancer samples harboring pathogenic mutations. Bisulfite-seq revealed a significant hypomethylation within promoter regions of mutated BRCA1 and BRCA2 genes in ovarian cancer samples, compared to non-mutated cases with pathogenic mutations, indicating the role of epigenetics in expression dysregulation as well. By uncovering clinically significant pathogenic mutations in BRCA1/2 genes and establishing their link with up-regulated gene expression, this study significantly advances our understanding of ovarian cancer's underlying causes in the Pakistani population.

Dataset Information

BRCA mutations in the manifestation and treatment of ovarian cancer.

Publications

BRCA mutations in the manifestation and treatment of ovarian cancer.

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