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Next-Generation Sequencing-based genomic profiling of brain metastases of primary ovarian cancer identifies high number of BRCA-mutations.

ABSTRACT: Ovarian cancer represents the most common gynaecological malignancy and has the highest mortality of all female reproductive cancers. It has a rare predilection to develop brain metastases (BM). In this study, we evaluated the mutational profile of ovarian cancer metastases through Next-Generation Sequencing (NGS) with the aim of identifying potential clinically actionable genetic alterations with options for small molecule targeted therapy. Library preparation was conducted using Illumina TruSight Rapid Capture Kit in combination with a cancer specific enrichment kit covering 94 genes. BRCA-mutations were confirmed by using TruSeq Custom Amplicon Low Input Kit in combination with a custom-designed BRCA gene panel. In our cohort all eight sequenced BM samples exhibited a multitude of variant alterations, each with unique molecular profiles. The 37 identified variants were distributed over 22 cancer-related genes (23.4%). The number of mutated genes per sample ranged from 3 to 7 with a median of 4.5. The most commonly altered genes were BRCA1/2, TP53, and ATM. In total, 7 out of 8 samples revealed either a BRCA1 or a BRCA2 pathogenic mutation. Furthermore, all eight BM samples showed mutations in at least one DNA repair gene. Our NGS study of BM of ovarian carcinoma revealed a significant number of BRCA-mutations beside TP53, ATM and CHEK2 mutations. These findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian cancer metastasizing to the brain. Based on these findings, pharmacological PARP inhibition could be one potential targeted therapeutic for brain metastatic ovarian cancer patients.

SUBMITTER: Balendran S

PROVIDER: S-EPMC5537326 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Next-Generation Sequencing-based genomic profiling of brain metastases of primary ovarian cancer identifies high number of BRCA-mutations.

Balendran S S Liebmann-Reindl S S Berghoff A S AS Reischer T T Popitsch N N Geier C B CB Kenner L L Birner P P Streubel B B Preusser M M

Journal of neuro-oncology 20170511 3

Ovarian cancer represents the most common gynaecological malignancy and has the highest mortality of all female reproductive cancers. It has a rare predilection to develop brain metastases (BM). In this study, we evaluated the mutational profile of ovarian cancer metastases through Next-Generation Sequencing (NGS) with the aim of identifying potential clinically actionable genetic alterations with options for small molecule targeted therapy. Library preparation was conducted using Illumina TruSi ...[more]

PMID: 28497333

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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

Next-Generation Sequencing-based genomic profiling of brain metastases of primary ovarian cancer identifies high number of BRCA-mutations.

Publications

Next-Generation Sequencing-based genomic profiling of brain metastases of primary ovarian cancer identifies high number of BRCA-mutations.

Similar Datasets

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