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.Electronic supplementary materialThe online version of this article (doi:10.1007/s11060-017-2459-z) contains supplementary material, which is available to authorized users.

Patterns of recurrence and metastasis in BRCA1/BRCA2‐associated breast cancers

“…25 Balendran et al reported a high rate of BRCA1 or BRCA2 mutations detected in the brain metastases of patients with ovarian cancer. 26 Of interest, platinum agents have demonstrated efficacy against brain metastases across many tumor types, including breast cancer, suggesting vulnerability of brain metastases to DNAdamaging agents. 27,28 Notably, our study included patients who received treatment before the regulatory approval of PARP inhibitors for the treatment of metastatic, BRCA1-associated or BRCA2-associated breast cancer.…”

Treatment Results and Prognostic Factors of Brain Metastases From Ovarian Cancer: A Single Institutional Experience of 56 Patients

“…25,26 Higher proportion of BRCA1 (Sekine et al 27 4/7 patients) and BRCA1/2 (Balendran et al, 28 7/8 patients) mutation suggested potential role of BRCA mutation in ovarian cancer metastasizing to brain. …”

Validation of Androgen Receptor loss as a risk factor for the development of brain metastases from ovarian cancers

“…Few clinical and molecular factors have been studied, such as CD133 overexpression and platinum resistance (18), overexpression of MDR-1 (multi drug resistance 1) (19), having suffered from a previous breast cancer (20), loss of BRCA function (21) and, presence of mutations in BRCA1 and BRCA2 genes (22). In our work we explored the predictive and prognostic role of AR.…”