Abstract
BackgroundBRCA1/2-deficient ovarian carcinomas are recognized as target for Poly (ADP-ribose) polymerase (PARP) inhibitors. BRCA1 and BRCA2 proteins are involved in homologous recombination repair of double-strand DNA breaks. The relevance of other homologous recombination repair proteins, e.g. MRE11, RAD50, NBS1 (MRN complex) in ovarian carcinomas is unclear. The objective of this study was to investigate the prevalence of lack of MRE11, RAD50, NBS1 protein detection in epithelial ovarian cancer (EOC).MethodsA tissue microarray (TMA) with 134 EOC was immunohistochemically evaluated for MRE11, RAD50 and NBS1. Data was analysed for associations with clinicopathological parameters, histological subtype, patient overall survival and mismatch repair (MMR) protein status. Sensitivity towards the PARP inhibitor BMN673 was tested in two ovarian cancer cell lines (TOV-21 and OVTOKO) using colony formation assays.ResultsLack of MRN complex protein detection was seen in 41% (55/134) of EOC and was more frequent in low-grade (57.6%; 19/33) than in high-grade EOC (18.8%; 36/101; n = 134; p = 0.04). There was an association with the ovarian carcinoma subtype (60.3%; 35/58 lack of detection in type I versus 26.3%; 20/76 in type II; n = 134; p < 0.001) as well as undetectable DNA mismatch repair proteins MLH1 and MSH2 (89.3%; 25/28; n = 131; p < 0.001). MRE11 knockdown led to moderately increased sensitivity towards the PARP inhibitor BMN673 in one ovarian carcinoma cell line in vitro.ConclusionsFrequent lack of MRE11, RAD50, NBS1 protein detection in type I human ovarian carcinomas is observed in EOC and our data suggests further investigation regarding sensitivity to PARP-inhibition in tumours lacking MRE11 expression.
Highlights
BRCA1/2-deficient ovarian carcinomas are recognized as target for Poly (ADP-ribose) polymerase (PARP) inhibitors
MRN complex detection and clinicopathological parameters Immunohistochemical analysis of MRE11, RAD50 and NBS1 was successful in a maximum of 134 carcinomas
MRE11, RAD50 and NBS1 Detection and Mismatch Repair Protein Detection We investigated mismatch repair protein expression by immunohistochemistry in a maximum of 133 ovarian carcinomas
Summary
BRCA1/2-deficient ovarian carcinomas are recognized as target for Poly (ADP-ribose) polymerase (PARP) inhibitors. BRCA1 and BRCA2 proteins are involved in homologous recombination repair of double-strand DNA breaks. The relevance of other homologous recombination repair proteins, e.g. MRE11, RAD50, NBS1 (MRN complex) in ovarian carcinomas is unclear. The objective of this study was to investigate the prevalence of lack of MRE11, RAD50, NBS1 protein detection in epithelial ovarian cancer (EOC). Germline BRCA1 and BRCA2 mutations account for about 10–15% of ovarian cancers and are mainly found in high-grade serous and endometrioid ovarian carcinomas [4, 5]. BRCA1 and BRCA2 are critical proteins in the process of homologous recombination repair (HR) of double-strand DNA breaks. In addition to BRCA1 and BRCA2, many other proteins are involved in the HR repair process of double-strand DNA breaks and are implicated in hereditary breast and ovarian
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