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https://www.readbyqxmd.com/read/29138572/current-status-of-poly-adp-ribose-polymerase-inhibitors-and-future-directions
#1
REVIEW
Akihiro Ohmoto, Shinichi Yachida
Inhibitors of poly(ADP-ribose) polymerases (PARPs), which play a key role in DNA damage/repair pathways, have been developed as antitumor agents based on the concept of synthetic lethality. Synthetic lethality is the idea that cell death would be efficiently induced by simultaneous loss of function of plural key molecules, for example, by exposing tumor cells with inactivating gene mutation of BRCA-mediated DNA repair to chemically induced inhibition of PARPs. Indeed, three PARP inhibitors, olaparib, rucaparib and niraparib have already been approved in the US or Europe, mainly for the treatment of BRCA-mutant ovarian cancer...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29138235/brip1-overexpression-is-correlated-with-clinical-features-and-survival-outcome-of-luminal-breast-cancer-subtypes
#2
Ishita Gupta, Allal Ouhtit, Adil Al-Ajmi, Syed Gauhar A Rizvi, Hamad Al-Riyami, Marwa Al-Riyami, Yahya Tamimi
In Oman, breast cancer is most common, representing approximately more than 25% of all cancers in women. Relatively younger populations of patients (25 to 40 years) present surprisingly with an aggressive phenotype and advanced tumor stages. In this study, we investigated differential gene expressions in Luminal-A, Luminal-B, Triple negative and Her2+ breast cancer subtypes and compared data to benign tumor samples. We identified a potential candidate gene BRIP1, showing differential expression in the four breast cancer subtypes examined, suggesting that BRIP1 has the profile of a useful diagnostic marker, suitable for targeted therapeutic intervention...
November 14, 2017: Endocrine Connections
https://www.readbyqxmd.com/read/29132683/-impairment-of-dna-damage-response-and-cancer
#3
REVIEW
Chloé Rancoule, Alexis Vallard, Jean-Baptiste Guy, Sophie Espenel, Sylvie Sauvaigo, Claire Rodriguez-Lafrasse, Nicolas Magné
Maintaining the genetic integrity is a key process in cell viability and is enabled by a wide network of repair pathways. When this system is defective, it generates genomic instability and results in an accumulation of chromosomal aberrations and mutations that may be responsible for various clinical phenotypes, including susceptibility to develop cancer. Indeed, these defects can promote not only the initiation of cancer, but also allow the tumor cells to rapidly acquire mutations during their evolution. Several genes are involved in these damage repair systems and particular polymorphisms are predictive of the onset of cancer, the best described of them being BRCA...
November 10, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/29128106/who-are-the-long-term-survivors-of-high-grade-serous-ovarian-cancer
#4
REVIEW
Claire Hoppenot, Mark A Eckert, Samantha M Tienda, Ernst Lengyel
Although the median survival for epithelial ovarian cancer (EOC) is <5years, approximately 15% of patients will survive for >10years. A better understanding of these exceptional responders could reveal opportunities to improve the dismal prognosis of most EOC patients. In this review, we examine the clinical and genomic features that have been associated with long-term survival, which is generally defined as survival of >7-10years after initial diagnosis. Clinical features influencing long-term survival have been best reported in large retrospective population-based studies...
November 8, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/29126396/feasibility-of-structured-endurance-training-and-mediterranean-diet-in-brca1-and-brca2-mutation-carriers-an-interventional-randomized-controlled-multicenter-trial-libre-1
#5
Marion Kiechle, Ricarda Dukatz, Maryam Yahiaoui-Doktor, Anika Berling, Maryam Basrai, Vera Staiger, Uwe Niederberger, Nicole Marter, Jacqueline Lammert, Sabine Grill, Katharina Pfeifer, Kerstin Rhiem, Rita K Schmutzler, Matthias Laudes, Michael Siniatchkin, Martin Halle, Stephan C Bischoff, Christoph Engel
BACKGROUND: Women with pathogenic BRCA germline mutations have an increased risk for breast and ovarian cancer that seems to be modified by life-style factors. Though, randomized trials investigating the impact of lifestyle interventions on cancer prevention and prognosis in BRCA carriers are still missing. METHODS: We implemented a multicenter, prospective randomized controlled trial in BRCA1/2 patients, comparing a lifestyle intervention group (IG) with a control group (CG) with the primary aim to prove feasibility...
November 10, 2017: BMC Cancer
https://www.readbyqxmd.com/read/29120748/doubling-down-on-brca-mutated-cancer
#6
Andrea E Wahner Hendrickson, Scott H Kaufmann, Elizabeth M Swisher
Immunotherapy is changing the landscape of cancer treatment. Nonetheless, not all malignancies respond, possibly due to low mutational load. Recent work in a TP53(-/-)BRCA1-mutant murine breast cancer model indicates that double blockade with two immune checkpoint inhibitors increases the number of tumor-infiltrating lymphocytes and overall survival after DNA damaging chemotherapy, whereas single blockade does not. These findings suggest an approach to enhance the impact of immune checkpoint blockade in BRCA-mutated tumors...
November 2017: Trends in Cancer
https://www.readbyqxmd.com/read/29116469/brca1-deficiency-is-a-recurrent-event-in-early-onset-triple-negative-breast-cancer-a-comprehensive-analysis-of-germline-mutations-and-somatic-promoter-methylation
#7
Rafael Canfield Brianese, Kivvi Duarte de Mello Nakamura, Fernanda Gabriella Dos Santos Ramos de Almeida, Rodrigo Fernandes Ramalho, Bruna Durães de Figueiredo Barros, Elisa Napolitano E Ferreira, Maria Nirvana da Cruz Formiga, Victor Piana de Andrade, Vladmir Claudio Cordeiro de Lima, Dirce Maria Carraro
PURPOSE: BRCA1 germline mutation is closely associated with triple-negative breast cancer. BRCA deficiency leads to impaired DNA repair and tumor development, and understanding this deficiency, in both hereditary and sporadic scenarios, is of great clinical and biological interest. Here, we investigated germline or somatic events that might lead to BRCA1 impairment in triple-negative breast cancer. We also analyzed the clinical implications associated with BRCA deficiency. METHODS: Next-generation sequencing for the BRCA1/2 genes and multiplex ligation-dependent probe amplification (MLPA) for the BRCA1 gene were performed for mutation screening...
November 7, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29109859/candidate-synthetic-lethality-partners-to-parp-inhibitors-in-the-treatment-of-ovarian-clear-cell-cancer
#8
Naoki Kawahara, Kenji Ogawa, Mika Nagayasu, Mai Kimura, Yoshikazu Sasaki, Hiroshi Kobayashi
Inhibitors of poly(ADP-ribose) polymerase (PARP) are new types of personalized treatment of relapsed platinum-sensitive ovarian cancer harboring BRCA1/2 mutations. Ovarian clear cell cancer (CCC), a subset of ovarian cancer, often appears as low-stage disease with a higher incidence among Japanese. Advanced CCC is highly aggressive with poor patient outcome. The aim of the present study was to determine the potential synthetic lethality gene pairs for PARP inhibitions in patients with CCC through virtual and biological screenings as well as clinical studies...
November 2017: Biomedical Reports
https://www.readbyqxmd.com/read/29108297/phase-i-ib-study-of-olaparib-and-carboplatin-in-women-with-triple-negative-breast-cancer
#9
Jung-Min Lee, John L Hays, Victoria L Chiou, Christina M Annunziata, Elizabeth M Swisher, Maria I Harrell, Minshu Yu, Nicolas Gordon, Tristan M Sissung, Jiuping Ji, William D Figg, Lori Minasian, Stanley Lipkowitz, Bradford J Wood, James Doroshow, Elise C Kohn
PURPOSE: To investigate the safety, activity, and potential biomarkers of response to olaparib and carboplatin combination in sporadic triple negative breast cancer (TNBC). EXPERIMENTAL DESIGN: Metastatic or recurrent TNBC patients with no germline BRCA mutation or with BRCAPro scores <10% and a negative family history were eligible. A 3+3 dose escalation tested olaparib capsules (400mg bid, days1-7) with carboplatin AUC3-5 on day1 or 2 every 21 days, ≤ 8 cycles, with olaparib 400mg bid maintenance...
October 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29096890/breast-cancer-epidemiology-prevention-and-screening
#10
Stella Winters, Charmaine Martin, Daniel Murphy, Navkiran K Shokar
Globally, breast cancer is both the most commonly occurring cancer and the commonest cause of cancer death among women. Available data suggest that incidence and mortality in high-resource countries has been declining whereas incidence and mortality in low-resource countries has been increasing. This pattern is likely to be due to changing risk factor profiles and differences in access to breast cancer early detection and treatment. Risk factors for breast cancer include increasing age, race, menarche history, breast characteristics, reproductive patterns, hormone use, alcohol use, tobacco use, diet, physical activity, and body habitus...
2017: Progress in Molecular Biology and Translational Science
https://www.readbyqxmd.com/read/29091556/olaparib-for-metastatic-germline-brca-mutated-breast-cancer
#11
LETTER
Mark Robson, Carsten Goessl, Susan Domchek
New England Journal of Medicine, Volume 377, Issue 18, Page 1792-1793, November 2017.
November 2, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29082482/germline-mutations-in-brca1-and-brca2-incidentally-revealed-in-a-biobank-research-study-experiences-from-re-contacting-mutation-carriers-and-relatives
#12
Martin P Nilsson, Monica Emmertz, Ulf Kristoffersson, Åke Borg, Christer Larsson, Martin Rehn, Christof Winter, Lao H Saal, Yvonne Brandberg, Niklas Loman
Once an incidental finding (IF) is discovered in the course of genomic research, the researchers are faced with the question of whether or not that finding should be reported back to the study participant. A large number of hypothetical studies and policy documents on this issue have been published, but there are very few empirical studies to inform the bioethics debate. Within a biobank research study of somatic mutations in breast carcinomas, ten germline BRCA1/2 mutations were incidentally detected. After thorough discussions within a group of experts, the mutation carriers (n = 7) or relatives of deceased carriers (n = 3) were re-contacted and informed about the findings...
October 30, 2017: Journal of Community Genetics
https://www.readbyqxmd.com/read/29081841/niraparib-in-ovarian-cancer-results-to-date-and-clinical-potential
#13
REVIEW
Davide Caruso, Anselmo Papa, Silverio Tomao, Patrizia Vici, Pierluigi Benedetti Panici, Federica Tomao
Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2, two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA-mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy...
September 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/29069866/germline-mutations-in-pancreatic-cancer-and-potential-new-therapeutic-options
#14
REVIEW
Rille Pihlak, Juan W Valle, Mairéad G McNamara
Due to short-lived treatment responses in unresectable disease, pancreatic ductal adenocarcinoma (PDAC) continues to be one of the deadliest cancers. There is availability of new information about germline and sporadic mutations in the deoxyribonucleic acid (DNA) damage repair pathway in PDAC in recent decades and the expectation is that novel targeted therapies will thus be developed. A variety of germline mutations (BRCA2, BRCA1, PALB2, CDKN2A, ATM, TP53 and mismatch repair genes MLH1, MSH2, MSH6) have been reported in these patients with the highest prevalence being BRCA1/2...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29063517/parp-inhibitors-in-the-treatment-of-triple-negative-breast-cancer
#15
REVIEW
Jill J J Geenen, Sabine C Linn, Jos H Beijnen, Jan H M Schellens
Breast cancer is a heterogeneous disease, manifesting in a broad differentiation in phenotypes and morphologic profiles, resulting in variable clinical behavior. Between 10 and 20% of all breast cancers are triple negative. Triple-negative breast cancer (TNBC) lacks the expression of human epidermal growth factor receptor 2 (HER2) and hormone receptors; therefore, to date, chemotherapy remains the backbone of treatment. TNBC tends to be aggressive and has a high histological grade, resulting in a poor 5-year prognosis...
October 23, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29061774/immune-checkpoint-inhibitors-in-gynecological-cancers-update-of-literature-and-perspectives-of-clinical-research
#16
REVIEW
Angiolo Gadducci, Maria Elena Guerrieri
The presence of tumor infiltrating lymphocytes (TILs) influences the clinical outcome of cancer patients and immune checkpoint inhibitors (ICPI) have been approved for treating different types of malignancies. In this review, we assess the scanty data from literature and the perspectives of clinical research about the use of ICPI in gynecological cancers. These agents have obtained objective response rates ranging from 5.9% to 15% in early phase Ib-II trials, including patients with platinum-resistant ovarian cancer, whereas only anecdotal data are available for patients with recurrent, heavily pretreated endometrial cancer...
November 2017: Anticancer Research
https://www.readbyqxmd.com/read/29061375/evaluation-of-a-next-generation-sequencing-assay-for-brca1-and-brca2-mutation-detection
#17
Gabriele Lorenzo Capone, Anna Laura Putignano, Sharon Trujillo Saavedra, Irene Paganini, Roberta Sestini, Francesca Gensini, Irene De Rienzo, Laura Papi, Berardino Porfirio
The efficiency of a novel targeted next-generation sequencing (NGS) test, the Devyser BRCA kit, for a comprehensive analysis of all 48 coding exons of the high-risk breast/ovarian cancer susceptibility genes BRCA1 and BRCA2 has been assessed. The new assay intended to detect nucleotide substitutions, small deletions/insertions, and large deletions/duplications. To document the false-negative and false-positive rates of the NGS assay in the hands of end-users, 48 samples with previously identified 444 small-size variants and seven gross rearrangements were analyzed, showing 100% concordance with gold standards...
October 20, 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/29058922/-satisfaction-and-overall-quality-of-life-in-brca-positive-women-after-prophylactic-surgeries
#18
P Šašková, D Pavlišta, L Dostálek
INTRODUCTION: Genetic mutations are responsible for 5-10% of all breast and ovarian carcinomas, while most of them are caused by a mutation of the BRCA gene. Women with this type of mutation have a lifetime risk of breast and ovarian cancer and therefore, they require very intensive medical care, including surgical prevention. Specifically, prophylactic bilateral mastectomy and prophylactic salpingo-oophorectomy are done, which undoubtedly decrease the riskof cancer. The aim of this review article is to inform healthcare professionals and the general public about the satisfaction of BRCA positive women with their decision to undergo these prophylactic surgeries, and also about the impact of these procedures on sexuality, menopausal symptoms, mental health and the overall quality of life...
2017: Rozhledy V Chirurgii: Měsíčník Československé Chirurgické Společnosti
https://www.readbyqxmd.com/read/29054544/-abnormalities-of-dna-repair-and-gynecological-cancers
#19
REVIEW
Aurélie Auguste, Alexandra Leary
The demonstration of frequent defects in the DNA damage response in high grade ovarian cancer has paved the way for a new therapeutic approach aimed at exploiting this unique vulnerability. The efficacy of poly (ADP) ribose polymerase inhibitors (PARPi) in patients with homologous recombination (HR) DNA repair deficient ovarian cancer (OC) resulting from a BRCA1/2 mutation has provided the proof of concept for synthetic lethality. Thus, olaparib is now approved by the EMA as maintenance therapy after response to a platinum regimen for patients with recurrent, platinum-sensitive, high-grade serous, BRCA1/2-mutated ovarian cancer...
October 17, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/29051491/fan1-interaction-with-ubiquitylated-pcna-alleviates-replication-stress-and-preserves-genomic-integrity-independently-of-brca2
#20
Antonio Porro, Matteo Berti, Julia Pizzolato, Serena Bologna, Svenja Kaden, Anja Saxer, Yue Ma, Kazuo Nagasawa, Alessandro A Sartori, Josef Jiricny
Interstrand cross-link (ICL) hypersensitivity is a characteristic trait of Fanconi anemia (FA). Although FANCD2-associated nuclease 1 (FAN1) contributes to ICL repair, FAN1 mutations predispose to karyomegalic interstitial nephritis (KIN) and cancer rather than to FA. Thus, the biological role of FAN1 remains unclear. Because fork stalling in FAN1-deficient cells causes chromosomal instability, we reasoned that the key function of FAN1 might lie in the processing of halted replication forks. Here, we show that FAN1 contains a previously-uncharacterized PCNA interacting peptide (PIP) motif that, together with its ubiquitin-binding zinc finger (UBZ) domain, helps recruit FAN1 to ubiquitylated PCNA accumulated at stalled forks...
October 20, 2017: Nature Communications
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