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      Ovarian Cancer and BRCA1/2 Testing: Opportunities to Improve Clinical Care and Disease Prevention

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          Abstract

          Without prevention or screening options available, ovarian cancer is the most lethal malignancy of the female reproductive tract. High-grade serous ovarian cancer (HGSOC) is the most common histologic subtype, and the role of germline BRCA1/2 mutation in predisposition and prognosis is established. Given the targeted treatment opportunities with PARP inhibitors, a predictive role for BRCA1/2 mutation has emerged. Despite recommendations to provide BRCA1/2 testing to all women with histologically confirmed HGSOC, uniform implementation remains challenging. The opportunity to review and revise genetic screening and testing practices will identify opportunities, where universal adoption of BRCA1/2 mutation testing will impact and improve treatment of women with ovarian cancer. Improving education and awareness of genetic testing for women with cancer, as well as the broader general community, will help focus much-needed attention on opportunities to advance prevention and screening programs in ovarian cancer. This is imperative not only for women with cancer and those at risk of developing cancer but also for their first-degree relatives. In addition, BRCA1/2 testing may have direct implications for patients with other types of cancers, many of which are now being found to have BRCA1/2 involvement.

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          Most cited references62

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          A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.

          A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.
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            Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition.

            Deficiency in either of the breast cancer susceptibility proteins BRCA1 or BRCA2 induces profound cellular sensitivity to the inhibition of poly(ADP-ribose) polymerase (PARP) activity. We hypothesized that the critical role of BRCA1 and BRCA2 in the repair of double-strand breaks by homologous recombination (HR) was the underlying reason for this sensitivity. Here, we examine the effects of deficiency of several proteins involved in HR on sensitivity to PARP inhibition. We show that deficiency of RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity. This suggests that BRCA-deficient cells are, at least in part, sensitive to PARP inhibition because of HR deficiency. These results indicate that PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutation-associated tumors but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway or displaying properties of 'BRCAness.'
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              Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.

              Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                11 May 2016
                2016
                : 6
                : 119
                Affiliations
                [1] 1Drug Development Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto , Toronto, ON, Canada
                Author notes

                Edited by: Sarah M. Temkin, National Cancer Institute, USA

                Reviewed by: Tamara Louise Kalir, The Mount Sinai School of Medicine, USA; Paola Gehrig, University of North Carolina, USA

                *Correspondence: Stephanie Lheureux, stephanie.lheureux@ 123456uhn.ca

                Specialty section: This article was submitted to Women’s Cancer, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2016.00119
                4862980
                27242959
                7b16c7a5-8b96-4fc4-b986-d241572b0af7
                Copyright © 2016 Karakasis, Burnier, Bowering, Oza and Lheureux.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 26 February 2016
                : 28 April 2016
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 97, Pages: 10, Words: 7476
                Categories
                Oncology
                Review

                Oncology & Radiotherapy
                ovarian cancer,brca1/2,testing,treatment,prevention
                Oncology & Radiotherapy
                ovarian cancer, brca1/2, testing, treatment, prevention

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