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

• Published in: Journal of neuro-oncology Vol. 133; no. 3; pp. 469 - 476
• Main Authors: Balendran, S., Liebmann-Reindl, S., Berghoff, A. S., Reischer, T., Popitsch, N., Geier, C. B., Kenner, L., Birner, P., Streubel, B., Preusser, M.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-07-2017; Springer Nature B.V
• Subjects: Adult; Aged; Ataxia Telangiectasia Mutated Proteins - genetics; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - secondary; BRCA1 protein; BRCA1 Protein - genetics; BRCA2 protein; BRCA2 Protein - genetics; Breast cancer; DNA repair; Female; Genes; Health risk assessment; High-Throughput Nucleotide Sequencing; Humans; Laboratory Investigation; Malignancy; Medicine; Medicine & Public Health; Metastases; Metastasis; Middle Aged; Mutation; Neurology; Oncology; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; p53 Protein; Poly(ADP-ribose) polymerase; Retrospective Studies; Tumor Suppressor Protein p53 - genetics; Brain metastases; Next-Generation Sequencing; Ovarian cancer; /; BRCA1/2; ATM; TP53
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1007/s11060-017-2459-z

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.