Increased single-strand annealing rather than non-homologous end-joining predicts hereditary ovarian carcinoma
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Miriam Deniz1, Tatiana Romashova1, Sarah Kostezka1, Anke Faul1, Theresa Gundelach1, Maria Moreno-Villanueva2, Wolfgang Janni1, Thomas W.P. Friedl1 and Lisa Wiesmüller1
1Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany
2Department of Biology, University of Konstanz, Konstanz, Germany
Lisa Wiesmüller, email: email@example.com
Miriam Deniz, email: firstname.lastname@example.org
Keywords: early-onset ovarian cancer; ovarian cancer risk; error-prone DNA repair; PARP activity; functional biomarker
Received: July 02, 2017 Accepted: August 26, 2017 Published: October 09, 2017
Mutations in genes encoding DNA double-strand break (DSB) repair components, especially homologous recombination (HR) proteins, were found to predispose to breast and ovarian cancer. Beyond high penetrance risk gene mutations underlying monogenic defects, low risk gene mutations generate polygenic defects, enlarging the fraction of individuals with a predisposing phenotype. DSB repair dysfunction opens new options for targeted therapies; poly (ADP-ribose) polymerase (PARP) inhibitors have been approved for BRCA-mutated and platinum-responsive ovarian cancers. In this work, we performed functional analyses in peripheral blood lymphocytes (PBLs) using a case-control design. We examined 38 women with familial history of breast and/or ovarian cancer, 40 women with primary ovarian cancer and 34 healthy controls. Using a GFP-based test we analyzed error-prone DSB repair mechanisms which are known to compensate for HR defects and to generate chromosomal instabilities. While non-homologous end-joining (NHEJ) did not discriminate between cases and controls, we found increases of single-strand annealing (SSA) in women with familial risk vs. controls (P=0.016) and patients with ovarian cancer vs. controls (P=0.002). Consistent with compromised HR we also detected increased sensitivities to carboplatin in PBLs from high-risk individuals (P<0.0001) as well as patients (P=0.0011) compared to controls. Conversely, neither PARP inhibitor responses nor PARP activities were altered in PBLs from the case groups, but PARP activities increased with age in high-risk individuals, providing novel clues for differential drug mode-of-action. Our findings indicate the great potential of detecting SSA activities to deliver an estimate of ovarian cancer susceptibility and therapeutic responsiveness beyond the limitations of genotyping.
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