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Breast cancer. Dna repair. Brca1. Brca2. Ovarian cancer

Steven J Isakoff, Shannon Puhalla, Susan M Domchek, Michael Friedlander, Bella Kaufman, Mark Robson, Melinda L Telli, Véronique Diéras, Hyo Sook Han, Judy E Garber, Eric F Johnson, David Maag, Qin Qin, Vincent L Giranda, Stacie P Shepherd
Veliparib is an orally administered poly(ADP-ribose) polymerase inhibitor that is being studied in Phase I-III clinical trials, including Phase III studies in non-small-cell lung cancer, ovarian cancer and breast cancer. Tumor cells with deleterious BRCA1 or BRCA2 mutations are deficient in homologous recombination DNA repair and are intrinsically sensitive to platinum therapy and poly(ADP-ribose) polymerase inhibitors. We describe herein the design and rationale of a Phase II trial investigating whether the addition of veliparib to temozolomide or carboplatin/paclitaxel provides clinical benefit over carboplatin/paclitaxel with placebo in patients with locally recurrent or metastatic breast cancer harboring a deleterious BRCA1 or BRCA2 germline mutation (Trial registration: EudraCT 2011-002913-12, NCT01506609)...
October 14, 2016: Future Oncology
Bradley J Monk, Domenica Lorusso, Antoine Italiano, Stan B Kaye, Miguel Aracil, Adnan Tanović, Maurizio D'Incalci
Trabectedin is a marine-derived product that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and the first anticancer marine drug to be approved by the European Union. It is currently used as a single agent for the treatment of patients with soft tissue sarcoma after failure of anthracyclines and ifosfamide, or for those patients who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin...
September 15, 2016: Cancer Treatment Reviews
Kritika Hanamshet, Olga M Mazina, Alexander V Mazin
Homologous recombination (HR) plays an important role in maintaining genomic integrity. It is responsible for repair of the most harmful DNA lesions, DNA double-strand breaks and inter-strand DNA cross-links. HR function is also essential for proper segregation of homologous chromosomes in meiosis, maintenance of telomeres, and resolving stalled replication forks. Defects in HR often lead to genetic diseases and cancer. Rad52 is one of the key HR proteins, which is evolutionarily conserved from yeast to humans...
2016: Genes
Finn Cilius Nielsen, Thomas van Overeem Hansen, Claus Storgaard Sørensen
Genetic abnormalities in the DNA repair genes BRCA1 and BRCA2 predispose to hereditary breast and ovarian cancer (HBOC). However, only approximately 25% of cases of HBOC can be ascribed to BRCA1 and BRCA2 mutations. Recently, exome sequencing has uncovered substantial locus heterogeneity among affected families without BRCA1 or BRCA2 mutations. The new pathogenic variants are rare, posing challenges to estimation of risk attribution through patient cohorts. In this Review article, we examine HBOC genes, focusing on their role in genome maintenance, the possibilities for functional testing of putative causal variants and the clinical application of new HBOC genes in cancer risk management and treatment decision-making...
September 2016: Nature Reviews. Cancer
Dominique Stoppa-Lyonnet
BRCA1 and BRCA2 are tumour-suppressor genes encoding proteins that are essential for the repair of DNA double-strand breaks by homologous recombination (HR). Cells that lack either BRCA1 or BRCA2 repair these lesions by alternative, more error-prone mechanisms. Individuals carrying germline pathogenic mutations in BRCA1 or BRCA2 are at highly elevated risk of developing breast and/or ovarian cancer. Genetic testing for germline pathogenic mutations in BRCA1 and BRCA2 has proved to be a valuable tool for determining eligibility for cancer screening and prevention programmes...
September 2016: European Journal of Human Genetics: EJHG
Marklie Munroe, Jill Kolesar
PURPOSE: The pharmacology, clinical efficacy, safety, dosage and administration, and role in therapy of olaparib, a first-in-class treatment for advanced treatment-refractory ovarian cancer, are reviewed. SUMMARY: Olaparib (Lynparza, AstraZeneca) is an oral inhibitor of poly(ADP-ribose) polymerase (PARP) proteins that play a key role in DNA repair and genomic stability. Olaparib is indicated for use in treating certain patients with advanced, recurrent ovarian cancer who have mutations of the breast cancer 1 gene (BRCA1) or breast cancer 2 gene (BRCA2)...
July 15, 2016: American Journal of Health-system Pharmacy: AJHP
Filipa Lynce, Claudine Isaacs
The traditional model by which an individual was identified as harboring a hereditary susceptibility to cancer was to test for a mutation in a single gene or a finite number of genes associated with a particular syndrome (e.g., BRCA1 and BRCA2 for hereditary breast and ovarian cancer or mismatch repair genes for Lynch syndrome). The decision regarding which gene or genes to test for was based on a review of the patient's personal medical history and their family history. With advances in next-generation DNA sequencing technology, offering simultaneous testing for multiple genes associated with a hereditary susceptibility to cancer is now possible...
2016: American Society of Clinical Oncology Educational Book
Kelly-Anne Phillips, Ian M Collins, Roger L Milne, Sue Anne McLachlan, Michael Friedlander, Martha Hickey, Catharyn Stern, John L Hopper, Richard Fisher, Gordon Kannemeyer, Sandra Picken, Charmaine D Smith, Thomas W Kelsey, Richard A Anderson
STUDY QUESTION: Do women with ITALIC! BRCA1 or ITALIC! BRCA2 mutations have reduced ovarian reserve, as measured by circulating anti-Müllerian hormone (AMH) concentration? SUMMARY ANSWER: Women with a germline mutation in ITALIC! BRCA1 have reduced ovarian reserve as measured by AMH. WHAT IS KNOWN ALREADY: The DNA repair enzymes encoded by ITALIC! BRCA1 and ITALIC! BRCA2 are implicated in reproductive aging. Circulating AMH is a biomarker of ovarian reserve and hence reproductive lifespan...
May 2016: Human Reproduction
Leslie M Randall, Bhavana Pothuri
Salient to the intent of personalized medicine, hereditary cancer syndromes present significant opportunities in the treatment and prevention of some gynecologic cancers. Mutations in BRCA1, BRCA2, and DNA mismatch repair genes: MLH1, MSH2, MSH6, and PMS2 are important causal agents in hereditary breast and ovarian cancer (HBOC) and Lynch syndromes. Though they only account for an estimated 10-18% of ovarian, tubal, peritoneal, and endometrial cancer cases, inherited cancers are imminently preventable if mutation carriers are identified in a timely manner...
April 2016: Gynecologic Oncology
Sudhir K Unni, Marisa B Schauerhamer, Rishi Deka, Jerzy E Tyczynski, Ancilla W Fernandes, Vanessa Stevens, Diana I Brixner, David D Stenehjem
BACKGROUND: Breast cancer associated (BRCA) genes are critical for DNA repair. Mutations in BRCA1 and BRCA2 (BRCAm) result in loss of these repair mechanisms and potential carcinogenesis. Germline BRCAm are common in ovarian carcinomas, particularly in platinum-sensitive disease. The increased prevalence of BRCAm in platinum-sensitive disease is likely due to enhanced responsiveness to platinum chemotherapy from homologous recombination repair deficiency. The purpose of this study was to explore BRCA testing, treatment patterns and survival in platinum-sensitive recurrent (PSR) ovarian cancer...
2016: Journal of Ovarian Research
Fei Huang, Nadish Goyal, Katherine Sullivan, Kritika Hanamshet, Mikir Patel, Olga M Mazina, Charles X Wang, W Frank An, James Spoonamore, Shailesh Metkar, Kyle A Emmitte, Simon Cocklin, Tomasz Skorski, Alexander V Mazin
RAD52 is a member of the homologous recombination (HR) pathway that is important for maintenance of genome integrity. While single RAD52 mutations show no significant phenotype in mammals, their combination with mutations in genes that cause hereditary breast cancer and ovarian cancer like BRCA1, BRCA2, PALB2 and RAD51C are lethal. Consequently, RAD52 may represent an important target for cancer therapy. In vitro, RAD52 has ssDNA annealing and DNA strand exchange activities. Here, to identify small molecule inhibitors of RAD52 we screened a 372,903-compound library using a fluorescence-quenching assay for ssDNA annealing activity of RAD52...
May 19, 2016: Nucleic Acids Research
Yi Du, Hirohito Yamaguchi, Yongkun Wei, Jennifer L Hsu, Hung-Ling Wang, Yi-Hsin Hsu, Wan-Chi Lin, Wen-Hsuan Yu, Paul G Leonard, Gilbert R Lee, Mei-Kuang Chen, Katsuya Nakai, Ming-Chuan Hsu, Chun-Te Chen, Ye Sun, Yun Wu, Wei-Chao Chang, Wen-Chien Huang, Chien-Liang Liu, Yuan-Ching Chang, Chung-Hsuan Chen, Morag Park, Philip Jones, Gabriel N Hortobagyi, Mien-Chie Hung
Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. One PARP inhibitor, olaparib (Lynparza, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with mutations in BRCA genes. BRCA1 and BRCA2 have essential roles in repairing DNA double-strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907)...
February 2016: Nature Medicine
Zohra Ali-Khan Catts, Muhammad Khurram Baig, Becky Milewski, Christine Keywan, Michael Guarino, Nicholas Petrelli
BACKGROUND: Considering the typical rapid progression and high mortality of pancreatic cancer (PC), early detection may lead to an improved outcome. To date, there is no safe, sensitive, and cost-effective screening strategy to detect PC. Currently, screening is focused on individuals at the highest risk of developing PC based on family history. A high-risk individual is defined as having two or more first-degree relatives with PC, or one first- or second-degree relative with PC with a confirmed mutation in a gene associated with PC...
May 2016: Annals of Surgical Oncology
M Janatová, M Borecká, J Soukupová, P Kleiblová, J Stříbrná, M Vočka, P Zemánková, A Panczak, K Veselá, P Souček, L Foretová, Z Kleibl
BACKGROUND: The PALB2 (FANCN) gene was identified as a component of endogenous BRCA2 complex that encodes a DNA repair protein participating along with BRCA1 and BRCA 2 proteins in DNA double-strand break repair. Hereditary PALB2 mutations are associated with an increased risk of breast and pancreatic cancers in heterozygotes. Breast cancer risk for PALB2 mutation carriers has recently been estimated at 33-58% depending on family history of breast cancer; pancreatic cancer risk in carriers of PALB2 mutations has not been precisely quantified, yet...
2016: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
Ludmil B Alexandrov, Serena Nik-Zainal, Hoi Cheong Siu, Suet Yi Leung, Michael R Stratton
Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double-strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum therapy exhibit this mutational signature including a sample that lacked any defects in BRCA1 or BRCA2...
October 29, 2015: Nature Communications
C Sénéchal, C Rousset-Jablonski
Should all women with BRCA1 or BRCA2 genes mutations be considered at risk of prematurely impaired fertility, and thus should a fertility preservation systematically be proposed? Women carrying mutations of BRCA1 or BRCA2 are at high risk for breast and tubo-ovarian cancer. The treatment of a breast cancer at a young age, unrare in this population, is associated with a risk of infertility, due to the ovarian toxicity of chemotherapy, to the recommended duration of hormonotherapy when indicated, and to the time advised before starting a pregnancy...
December 2015: Gynécologie, Obstétrique & Fertilité
Yosuke Hirotsu, Hiroshi Nakagomi, Ikuko Sakamoto, Kenji Amemiya, Toshio Oyama, Hitoshi Mochizuki, Masao Omata
Approximately 5-10% of all breast and/or ovarian cancer cases are considered as inherited. BRCA1 and BRCA2 tumor suppressor genes account for a high penetrance of hereditary cases, but familial cases without mutations in these genes can also occur. Despite their low penetrance, other hereditary cancer-related genes are known to be associated with breast and ovarian cancer risk. However, the extent to which these genes prevail in breast and ovarian cancer remains to be elucidated. To estimate the frequency of mutations in these predisposition genes, we analyzed the germline mutations of 25 hereditary cancer-related genes in 155 patients using targeted next-generation sequencing...
September 2015: Molecular Genetics & Genomic Medicine
Valérie Schreiber, Giuditta Illuzzi, Eléa Héberlé, Françoise Dantzer
Poly(ADP-ribosyl)ation is a post-translational modification catalyzed by poly(ADP-ribose) polymerases. PARP-1 is a molecular sensor of DNA breaks, playing a key role in the spatial and temporal organization of their repair, contributing to the maintenance of genome integrity and cell survival. The fact that PARP inhibition impairs efficacy of break repair has been exploited as anticancer strategies to potentiate the cytotoxicity of anticancer drugs and radiotherapy. Numerous clinical trials based on this innovative approach are in progress...
October 2015: Bulletin du Cancer
Luca Livraghi, Judy E Garber
Poly(ADP-ribose) polymerases (PARP) are enzymes involved in DNA-damage repair. Inhibition of PARPs is a promising strategy for targeting cancers with defective DNA-damage repair, including BRCA1 and BRCA2 mutation-associated breast and ovarian cancers. Several PARP inhibitors are currently in trials in the adjuvant, neoadjuvant, and metastatic settings for the treatment of ovarian, BRCA-mutated breast, and other cancers. We herein review the development of PARP inhibitors and the basis for the excitement surrounding these agents, their use as single agents and in combinations, as well as their toxicities, mechanisms of acquired resistance, and companion diagnostics...
2015: BMC Medicine
Frédéric Ancot, Suzanna L Arcand, Anne-Marie Mes-Masson, Diane M Provencher, Patricia N Tonin
French Canadian families with breast cancer and breast-ovarian cancer syndrome harbor specific BRCA1, BRCA2 and PALB2 germline mutations, which have been attributed to common founders. Mutations in these genes confer an increased risk to breast and ovarian cancers, and have been identified to play a role in and directly interact with the common homologous recombination DNA repair pathways. Our previous study described the case of a female diagnosed with breast cancer at 45 years old, who harbored the PALB2:c...
June 2015: Oncology Letters
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