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RAD51C breast ovarian cancer

Anya Alayev, Rachel S Salamon, Subrata Manna, Naomi S Schwartz, Adi Y Berman, Marina K Holz
Homologous recombination (HR) is a conserved process that maintains genome stability and cell survival by repairing DNA double-strand breaks (DSBs). The RAD51-related family of proteins is involved in repair of DSBs; consequently, deregulation of RAD51 causes chromosomal rearrangements and stimulates tumorigenesis. RAD51C has been identified as a potential tumor suppressor and a breast and ovarian cancer susceptibility gene. Recent studies have also implicated estrogen as a DNA-damaging agent that causes DSBs...
October 18, 2016: Cell Cycle
Rossella Graffeo, Luca Livraghi, Olivia Pagani, Aron Goldhirsch, Ann H Partridge, Judy E Garber
PURPOSE: Genetic evaluation is increasingly becoming an integral part of the management of women with newly diagnosed breast and ovarian cancer (OC), and of individuals at high risk for these diseases. Genetic counseling and testing have been incorporated into oncological care to help and complete management and treatment strategies. Risk assessment and early detection strategies in individuals with BRCA1/2 mutations and with Lynch syndrome have been quite extensively studied, whereas much less is known about the management of mutation carriers with less common high-penetrance cancer susceptibility genes (PTEN, TP53, STK11, CDH1), and particularly those who carry mutations in moderate-penetrance genes (e...
October 12, 2016: Breast Cancer Research and Treatment
Guido Neidhardt, Alexandra Becker, Jan Hauke, Judit Horváth, Nadja Bogdanova Markov, Stefanie Heilmann-Heimbach, Heide Hellebrand, Holger Thiele, Janine Altmüller, Peter Nürnberg, Alfons Meindl, Kerstin Rhiem, Britta Blümcke, Barbara Wappenschmidt, Rita K Schmutzler, Eric Hahnen
Whereas RAD51C mutations increase the relative risk for ovarian cancer (OC) to 5.88 (95% confidence interval=2.91-11.88, P=7.65×10), the associated risks for breast cancer (BC) remain largely unknown, as deleterious RAD51C alterations are extremely rare in BC-only families. Here, we report the results of a RAD51C mutational screening in a large series of German familial index patients negative for pathogenic BRCA1/2 mutations and the in-vitro characterization of two novel exonic RAD51C splice-site mutations...
September 10, 2016: European Journal of Cancer Prevention
Cornelia Kraus, Juliane Hoyer, Georgia Vasileiou, Marius Wunderle, Michael P Lux, Peter A Fasching, Mandy Krumbiegel, Steffen Uebe, Miriam Reuter, Matthias W Beckmann, André Reis
Breast and ovarian cancer (BC/OC) predisposition has been attributed to a number of high- and moderate to low-penetrance susceptibility genes. With the advent of next generation sequencing (NGS) simultaneous testing of these genes has become feasible. In this monocentric study, we report results of panel-based screening of 14 BC/OC susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, CHEK2, PALB2, ATM, NBN, CDH1, TP53, MLH1, MSH2, MSH6 and PMS2) in a group of 581 consecutive individuals from a German population with BC and/or OC fulfilling diagnostic criteria for BRCA1 and BRCA2 testing including 179 with a triple-negative tumor...
September 12, 2016: International Journal of Cancer. Journal International du Cancer
Karl Hackmann, Franziska Kuhlee, Elitza Betcheva-Krajcir, Anne-Karin Kahlert, Luisa Mackenroth, Barbara Klink, Nataliya Di Donato, Andreas Tzschach, Karin Kast, Pauline Wimberger, Evelin Schrock, Andreas Rump
PURPOSE: Detection of predisposing copy number variants (CNV) in 330 families affected with hereditary breast and ovarian cancer (HBOC). METHODS: In order to complement mutation detection with Illumina's TruSight Cancer panel, we designed a customized high-resolution 8 × 60k array for CGH (aCGH) that covers all 94 genes from the panel. RESULTS: Copy number variants with immediate clinical relevance were detected in 12 families (3.6%). Besides 3 known CNVs in CHEK2, RAD51C, and BRCA1, we identified 3 novel pathogenic CNVs in BRCA1 (deletion of exons 4-13, deletion of exons 12-18) and ATM (deletion exons 57-63) plus an intragenic duplication of BRCA2 (exons 3-11) and an intronic BRCA1 variant with unknown pathogenicity...
October 2016: Breast Cancer Research and Treatment
Muhammad U Rashid, Humaira Naeemi, Noor Muhammad, Asif Loya, Muhammed A Yusuf, Jan Lubiński, Anna Jakubowska, Ute Hamann
BACKGROUND: Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS) account for a significant proportion of inherited gynecologic malignancies, mainly caused by pathogenic germline mutations in the BRCA1 and BRCA2 genes or in mismatch repair (MMR) genes, such as MLH1 and MSH2. Women harboring deleterious mutations in these genes have increased life-time risks of developing a number of malignancies including ovarian cancer. Since there is a phenotypic overlap of HBOC and LS, timely identification of individuals at-risk of a particular syndrome is crucial in order to optimize cancer risk management...
2016: Hereditary Cancer in Clinical Practice
Nadine Tung, Nancy U Lin, John Kidd, Brian A Allen, Nanda Singh, Richard J Wenstrup, Anne-Renee Hartman, Eric P Winer, Judy E Garber
PURPOSE: Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population...
May 1, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
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
E Macháčková, J Hazova, E Sťahlová Hrabincová, P Vašíčková, M Navrátilová, M Svoboda, L Foretová
BACKGROUND: Currently, more than 200 hereditary cancer syndromes have been described, yet, in most countries genetic testing is restricted to a narrow spectrum of genes within a limited group of people tested. METHODS: For this retrospective study we used the TruSight cancer panel (Illumina)--NGS panel targeting 94 cancer predisposition genes in order to analyze 50 high-risk cancer patients with significant personal and family history of cancer who did not carry mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6, TP53 or APC genes...
2016: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
Tamar Yablonski-Peretz, Shani Paluch-Shimon, Lior Soussan Gutman, Yulia Kaplan, Addie Dvir, Inbal Barnes-Kedar, Luna Kadouri, Valeriya Semenisty, Noa Efrat, Victoria Neiman, Yafit Glasser, Rachel Michaelson-Cohen, Lior Katz, Bella Kaufman, Talia Golan, Orit Reish, Ayala Hubert, Tamar Safra, Yuval Yaron, Eitan Friedman
We evaluated the clinical utility of screening for mutations in 34 breast/ovarian cancer susceptibility genes in high-risk families in Israel. Participants were recruited from 12, 2012 to 6, 2015 from 8 medical centers. All participants had high breast/ovarian cancer risk based on personal and family history. Genotyping was performed with the InVitae™ platform. The study was approved by the ethics committees of the participating centers; all participants gave a written informed consent before entering the study...
January 2016: Breast Cancer Research and Treatment
Jun Li, Huong Meeks, Bing-Jian Feng, Sue Healey, Heather Thorne, Igor Makunin, Jonathan Ellis, Ian Campbell, Melissa Southey, Gillian Mitchell, David Clouston, Judy Kirk, David Goldgar, Georgia Chenevix-Trench
INTRODUCTION: Gene panel testing for breast cancer susceptibility has become relatively cheap and accessible. However, the breast cancer risks associated with mutations in many genes included in these panels are unknown. METHODS: We performed custom-designed targeted sequencing covering the coding exons of 17 known and putative breast cancer susceptibility genes in 660 non-BRCA1/2 women with familial breast cancer. Putative deleterious mutations were genotyped in relevant family members to assess co-segregation of each variant with disease...
January 2016: Journal of Medical Genetics
Ana Krivokuca, Kira Yanowski, Jelena Rakobradovic, Javier Benitez, Mirjana Brankovic-Magic
BACKGROUND: In 2010 an important finding was published showing that heterozygous mutations in RAD51C were highly penetrant and were able to confer an increased risk for breast and ovarian cancers. The role of possible third high penetrance breast cancer susceptibility gene was assigned to RAD51C. OBJECTIVE: Because of its rising importance in breast cancer development and the lack of information about RAD51C in Slavic populations, our goal was to identify potential population specific mutations in this gene in order to determine more detailed genetic screening strategy and breast cancer risk assessment...
2015: Cancer Biomarkers: Section A of Disease Markers
Kumar Somyajit, Sneha Saxena, Sharath Babu, Anup Mishra, Ganesh Nagaraju
Mammalian RAD51 paralogs are implicated in the repair of collapsed replication forks by homologous recombination. However, their physiological roles in replication fork maintenance prior to fork collapse remain obscure. Here, we report on the role of RAD51 paralogs in short-term replicative stress devoid of DSBs. We show that RAD51 paralogs localize to nascent DNA and common fragile sites upon replication fork stalling. Strikingly, RAD51 paralogs deficient cells exhibit elevated levels of 53BP1 nuclear bodies and increased DSB formation, the latter being attributed to extensive degradation of nascent DNA at stalled forks...
November 16, 2015: Nucleic Acids Research
Liisa M Pelttari, Laura Kinnunen, Johanna I Kiiski, Sofia Khan, Carl Blomqvist, Kristiina Aittomäki, Heli Nevanlinna
Several high and moderate risk alleles have been identified for breast and ovarian cancer predisposition and most of them encode proteins that function in DNA repair. A prospective candidate for breast and ovarian cancer susceptibility is the HELQ helicase that has a role in the resolution of DNA interstrand cross-links. HELQ interacts with the RAD51 paralog complex BCDX2. Two components of the complex, RAD51C and RAD51D, increase the risk of ovarian cancer especially, and the other two, RAD51B and XRCC2 have been associated with breast cancer risk...
January 2016: Familial Cancer
Liisa M Pelttari, Johanna I Kiiski, Salla Ranta, Sara Vilske, Carl Blomqvist, Kristiina Aittomäki, Heli Nevanlinna
Majority of the known breast cancer susceptibility genes have a role in DNA repair and the most important high-risk genes BRCA1 and BRCA2 are specifically involved in the homologous recombination repair (HRR) of DNA double-strand breaks. A central player in HRR is RAD51 that binds DNA at the damage site. The RAD51 paralogs RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3 facilitate the binding of RAD51 to DNA. While germline mutations in RAD51C and RAD51D are associated with high ovarian cancer risk and RAD51B polymorphisms with breast cancer, the contribution of RAD51, XRCC3, and XRCC2 is more unclear...
2015: SpringerPlus
V Sopik, M R Akbari, S A Narod
Much of the observed familial clustering of breast and ovarian cancer cannot be explained by mutations in BRCA1 and BRCA2. Several other cancer susceptibility genes have been identified, but their value in routine clinical genetic testing is still unclear. Germline mutations in RAD51C have been identified in about 1% of hereditary breast and ovarian cancer families. RAD51C mutations are predominantly found in families with a history of ovarian cancer and are rare in families with a history of breast cancer alone...
October 2015: Clinical Genetics
Fergus J Couch, Steven N Hart, Priyanka Sharma, Amanda Ewart Toland, Xianshu Wang, Penelope Miron, Janet E Olson, Andrew K Godwin, V Shane Pankratz, Curtis Olswold, Seth Slettedahl, Emily Hallberg, Lucia Guidugli, Jaime I Davila, Matthias W Beckmann, Wolfgang Janni, Brigitte Rack, Arif B Ekici, Dennis J Slamon, Irene Konstantopoulou, Florentia Fostira, Athanassios Vratimos, George Fountzilas, Liisa M Pelttari, William J Tapper, Lorraine Durcan, Simon S Cross, Robert Pilarski, Charles L Shapiro, Jennifer Klemp, Song Yao, Judy Garber, Angela Cox, Hiltrud Brauch, Christine Ambrosone, Heli Nevanlinna, Drakoulis Yannoukakos, Susan L Slager, Celine M Vachon, Diana M Eccles, Peter A Fasching
PURPOSE: Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. PATIENTS AND METHODS: Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations...
February 1, 2015: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Masami Arai, Takuji Iwase, Yutaka Takazawa, Nobuhiro Takeshima
The recognition of hereditary breast and ovarian cancer (HBOC) is gradually spreading in Japan after a famous American actress made it public that she underwent risk-reducing mastectomy (RRM) based on mutation of BRCA1. HBOC is a cancer susceptibility syndrome involving breast, ovarian, or prostate cancers due to germline mutation of BRCA1 or BRCA2. Although the frequency is low, genomic rearrangement is also found in Japan; therefore, in addition to PCR-direct sequencing, multiplex ligation-dependent probe amplification (MLPA) should be performed in genetic testing for HBOC...
November 2014: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Kumar Somyajit, Anup Mishra, Aida Jameei, Ganesh Nagaraju
Poly (ADP-ribose) polymerase 1 (PARP1) inhibitors are actively under clinical trials for the treatment of breast and ovarian cancers that arise due to mutations in BRCA1 and BRCA2. The RAD51 paralog RAD51C has been identified as a breast and ovarian cancer susceptibility gene. The pathological RAD51C mutants that were identified in cancer patients are hypomorphic with partial repair function. However, targeting cancer cells that express hypomorphic mutants of RAD51C is highly challenging. Here, we report that RAD51C-deficient cells can be targeted by a 'synthetic lethal' approach using PARP inhibitor and this sensitivity was attributed to accumulation of cells in the G2/M and chromosomal aberrations...
January 2015: Carcinogenesis
Manuela Tumiati, Annabrita Hemmes, Sanna Uusivirta, Sonja Koopal, Matti Kankainen, Eero Lehtonen, Sergey G Kuznetsov
Germline mutations in RAD51C predispose to breast and ovarian cancers. However, the mechanism of RAD51C-mediated carcinogenesis is poorly understood. We previously reported a first-generation Rad51c-knock-out mouse model, in which a spontaneous loss of both Rad51c and Trp53 together resulted in a high incidence of sebaceous carcinomas, particularly in preputial glands. Here we describe a second-generation mouse model, in which Rad51c is deleted, alone or together with Trp53, in sebaceous glands, using Cre-mediated recombination...
January 2015: Journal of Pathology
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