Increased single-strand annealing rather than non-homologous end-joining predicts hereditary ovarian carcinoma

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2017
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Deniz, Miriam
Romashova, Tatiana
Kostezka, Sarah
Faul, Anke
Gundelach, Theresa
Janni, Wolfgang
Friedl, Thomas W. P.
Wiesmüller, Lisa
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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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ISO 690DENIZ, Miriam, Tatiana ROMASHOVA, Sarah KOSTEZKA, Anke FAUL, Theresa GUNDELACH, Maria MORENO-VILLANUEVA, Wolfgang JANNI, Thomas W. P. FRIEDL, Lisa WIESMÜLLER, 2017. Increased single-strand annealing rather than non-homologous end-joining predicts hereditary ovarian carcinoma. In: Oncotarget. 2017, 8(58), pp. 98660-98676. eISSN 1949-2553. Available under: doi: 10.18632/oncotarget.21720
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@article{Deniz2017-11-17Incre-41548,
  year={2017},
  doi={10.18632/oncotarget.21720},
  title={Increased single-strand annealing rather than non-homologous end-joining predicts hereditary ovarian carcinoma},
  number={58},
  volume={8},
  journal={Oncotarget},
  pages={98660--98676},
  author={Deniz, Miriam and Romashova, Tatiana and Kostezka, Sarah and Faul, Anke and Gundelach, Theresa and Moreno-Villanueva, Maria and Janni, Wolfgang and Friedl, Thomas W. P. and Wiesmüller, Lisa}
}
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    <dcterms:abstract xml:lang="eng">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&lt;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.</dcterms:abstract>
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