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https://www.readbyqxmd.com/read/29321523/integrative-genomic-and-transcriptomic-analysis-of-leiomyosarcoma
#1
Priya Chudasama, Sadaf S Mughal, Mathijs A Sanders, Daniel Hübschmann, Inn Chung, Katharina I Deeg, Siao-Han Wong, Sophie Rabe, Mario Hlevnjak, Marc Zapatka, Aurélie Ernst, Kortine Kleinheinz, Matthias Schlesner, Lina Sieverling, Barbara Klink, Evelin Schröck, Remco M Hoogenboezem, Bernd Kasper, Christoph E Heilig, Gerlinde Egerer, Stephan Wolf, Christof von Kalle, Roland Eils, Albrecht Stenzinger, Wilko Weichert, Hanno Glimm, Stefan Gröschel, Hans-Georg Kopp, Georg Omlor, Burkhard Lehner, Sebastian Bauer, Simon Schimmack, Alexis Ulrich, Gunhild Mechtersheimer, Karsten Rippe, Benedikt Brors, Barbara Hutter, Marcus Renner, Peter Hohenberger, Claudia Scholl, Stefan Fröhling
Leiomyosarcoma (LMS) is an aggressive mesenchymal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. Here we show, using whole-exome and transcriptome sequencing, that LMS tumors are characterized by substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations including chromothripsis, and frequent whole-genome duplication. Furthermore, we detect alternative telomere lengthening in 78% of cases and identify recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and SP100, providing insight into the genetic basis of this mechanism...
January 10, 2018: Nature Communications
https://www.readbyqxmd.com/read/29300815/inhibited-trapped-or-adducted-the-optimal-selective-synthetic-lethal-mix-for-brcaness
#2
Andrew Tutt
No abstract text is available yet for this article.
December 28, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29287922/gynaecological-neoplasms-in-common-familial-syndromes-lynch-and-hboc
#3
REVIEW
Carla Bartosch, Blaise Clarke, Tjalling Bosse
Recognising hereditary predisposition in a cancer patient has implications both for the patient and the patient's kindred. For the latter, cascade germline testing can reassure those not-at-risk family members while carriers can be enrolled in cancer screening and prevention programs that are medically effective and economically sustainable for health care systems. Furthermore, in many of these syndromes, ramifications of molecular phenotypes are increasing, and it is now emerging that, in addition, they convey prognostic and predictive information...
December 26, 2017: Pathology
https://www.readbyqxmd.com/read/29260919/the-development-of-parp-as-a-successful-target-for-cancer-therapy
#4
Roberto Ferrara, Francesca Simionato, Chiara Ciccarese, Elisabetta Grego, Sara Cingarlini, Roberto Iacovelli, Emilio Bria, Giampaolo Tortora, Davide Melisi
PARP1 and BRCA genes are essential genome caretakers and their interaction has been the first example of synthetic lethality, a genetic concept proposed in the early 20th century, but deeply explored in cancer patients only in the last decade. Areas covered: This review describes PARP1 and BRCA main functions and different roles in genome protection. Furthermore, an overview of the principle mechanisms of action and resistance to PARP inhibitors (PARPi) is presented. This review illustrates the concept of BRCAness, and how this discovery has broadened the routes of PARPi to several different malignancies such as ovarian, breast and prostate cancer...
December 20, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29259228/metabolomics-reveals-novel-blood-plasma-biomarkers-associated-to-the-brca1-mutated-phenotype-of-human-breast-cancer
#5
Bàrbara Roig, Marta Rodríguez-Balada, Sara Samino, Eric W-F Lam, Sandra Guaita-Esteruelas, Ana R Gomes, Xavier Correig, Joan Borràs, Oscar Yanes, Josep Gumà
Hereditary breast and ovarian cancer syndrome (HBOC) is partly due to the presence of mutations in the BRCA genes. Triple-negative (TN) breast cancer (BC) shares histological characteristics with germline BRCA1 mutation-associated tumours. We have investigated the metabolic profiles of human breast cancer (BC) cell lines carrying BRCA1 pathogenic mutations by non-targeted liquid chromatography coupled to mass spectrometry technology. Based on our in vitro results, we performed a targeted metabolomic analysis of plasma samples from TN HBOC patients taking into account their BRCA1 genotype...
December 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29212150/combining-enzalutamide-with-parp-inhibitors-pharmaceutically-induced-brcaness
#6
EDITORIAL
Timothy C Thompson, Likun Li, Bradley M Broom
No abstract text is available yet for this article.
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29177481/cdyl1-fosters-double-strand-break-induced-transcription-silencing-and-promotes-homology-directed-repair
#7
Enas R Abu-Zhayia, Samah W Awwad, Bella Ben-Oz, Hanan Khoury-Haddad, Nabieh Ayoub
Cells have evolved DNA damage response (DDR) to repair DNA lesions and thus preserving genomic stability and impeding carcinogenesis. DNA damage induction is accompanied by transient transcription repression. Here, we describe a previously unrecognized role of chromodomain Y-like (CDYL1) protein in fortifying double-strand break (DSB)-induced transcription repression and repair. We showed that CDYL1 is rapidly recruited to damaged euchromatic regions in a poly [ADP-ribose] polymerase 1 (PARP1)-dependent, but ataxia telangiectasia mutated (ATM)-independent, manner...
November 21, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/29146938/computational-investigation-of-homologous-recombination-dna-repair-deficiency-in-sporadic-breast-cancer
#8
Yue Wang, Matthew H Ung, Sharon Cantor, Chao Cheng
BRCAness has important implications in the management and treatment of patients with breast and ovarian cancer. In this study, we propose a computational framework to measure the BRCAness of breast and ovarian tumor samples based on their gene expression profiles. We define a characteristic profile for BRCAness by comparing gene expression differences between BRCA1/2 mutant familial tumors and sporadic breast cancer tumors while adjusting for relevant clinical factors. With this BRCAness profile, our framework calculates sample-specific BRCA scores, which indicates homologous recombination (HR)-mediated DNA repair pathway activity of samples...
November 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28898201/aurka-inhibition-mimics-brcaness
#9
Jeff Hirst, Andrew K Godwin
No abstract text is available yet for this article.
September 11, 2017: Aging
https://www.readbyqxmd.com/read/28890386/co-targeting-c-met-and-dna-double-strand-breaks-dsbs-therapeutic-strategies-in-brca-mutated-gastric-carcinomas
#10
REVIEW
Chrysovalantou Mihailidou, Michalis V Karamouzis, Dimitrios Schizas, Athanasios G Papavassiliou
Gastric cancer (GC) is a threatening malignancy characterized by heterogeneity. Current therapies use DNA damaging agents, for example, chemotherapeutic agents and ionizing radiation (IR). However, a significant portion of GC patients develops therapeutic resistance to DNA damage response (DDR) - inducing agents. An important mechanism is the stimulation of the c-MET RTK, which is a tyrosine kinase receptor and its ligand hepatocyte growth factor (HGF), which facilitates cell survival by boosting DNA damage repair pathways and via escaping cell cycle arrest...
November 2017: Biochimie
https://www.readbyqxmd.com/read/28881597/tgfbeta-and-mirna-regulation-in-familial-and-sporadic-breast-cancer
#11
Katia Danza, Simona De Summa, Rosamaria Pinto, Brunella Pilato, Orazio Palumbo, Massimo Carella, Ondina Popescu, Maria Digennaro, Rosanna Lacalamita, Stefania Tommasi
The term 'BRCAness' was introduced to identify sporadic malignant tumors sharing characteristics similar to those germline BRCA-related. Among all mechanisms attributable to BRCA1 expression silencing, a major role has been assigned to microRNAs. MicroRNAs role in familial and sporadic breast cancer has been explored but few data are available about microRNAs involvement in homologous recombination repair control in these breast cancer subgroups. Our aim was to seek microRNAs associated to pathways underlying DNA repair dysfunction in breast cancer according to a family history of the disease...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28879638/impact-of-etoposide-on-brca1-expression-in-various-breast-cancer-cell-lines
#12
Xi Zhang, Simone Hofmann, Nadia Harbeck, Udo Jeschke, Sophie Sixou
Breast cancer 1 (BRCA1), as a tumor suppressor, exerts an effective influence on protecting DNA integrity to suppress the development of breast cancer (BC). BRCA1 expression is induced in response to DNA-damaging agents such as etoposide. Germline BRCA1 gene mutations are associated with development of hereditary BC. However, besides BRCA-mutated BCs, some sporadic cancers may also exhibit a BRCA-like phenotype, displaying so-called 'BRCAness'. This common phenotype may respond to similar therapeutic approaches as BRCA-mutated tumors and may thus have important implications for the clinical management of these cancers...
December 2017: Drugs in R&D
https://www.readbyqxmd.com/read/28617445/acquired-cross-linker-resistance-associated-with-a-novel-spliced-brca2-protein-variant-for-molecular-phenotyping-of-brca2-disruption
#13
Stefan Meyer, Adam Stevens, Roberto Paredes, Marion Schneider, Michael J Walker, Andrew J K Williamson, Maria-Belen Gonzalez-Sanchez, Stephanie Smetsers, Vineet Dalal, Hsiang Ying Teng, Daniel J White, Sam Taylor, Joanne Muter, Andrew Pierce, Chiara de Leonibus, Davy A P Rockx, Martin A Rooimans, Elaine Spooncer, Stacey Stauffer, Kajal Biswas, Barbara Godthelp, Josephine Dorsman, Peter E Clayton, Shyam K Sharan, Anthony D Whetton
BRCA2 encodes a protein with a fundamental role in homologous recombination that is essential for normal development. Carrier status of mutations in BRCA2 is associated with familial breast and ovarian cancer, while bi-allelic BRCA2 mutations can cause Fanconi anemia (FA), a cancer predisposition syndrome with cellular cross-linker hypersensitivity. Cancers associated with BRCA2 mutations can acquire chemo-resistance on relapse. We modeled acquired cross-linker resistance with an FA-derived BRCA2-mutated acute myeloid leukemia (AML) platform...
June 15, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28569220/brca-promoter-methylation-in-sporadic-versus-brca-germline-mutation-related-breast-cancers
#14
Shoko Vos, Cathy Beatrice Moelans, Paul Joannes van Diest
BACKGROUND: In breast cancer, BRCA promoter hypermethylation and BRCA germline mutations are said to occur together rarely, but this property has not yet been translated into a clinical test. Our aim in this study was to investigate the diagnostic value of BRCA1/2 methylation in distinguishing breast carcinomas of BRCA1 and BRCA2 germline mutation carriers from sporadic breast carcinomas using a recently developed BRCA methylation assay based on methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA)...
May 31, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28546758/distinct-implications-of-different-brca-mutations-efficacy-of-cytotoxic-chemotherapy-parp-inhibition-and-clinical-outcome-in-ovarian-cancer
#15
REVIEW
Robert L Hollis, Michael Churchman, Charlie Gourley
Approximately a fifth of ovarian carcinoma (OC) is associated with inherited germline mutations, most commonly in the DNA repair genes BRCA1 or BRCA2 (BRCA). BRCA1- and BRCA2-associated OCs have historically been described as a single subgroup of OC that displays a distinct set of characteristics termed the "BRCAness" phenotype. The hallmarks of this phenotype are superior clinical outcome and hypersensitivity to platinum-based chemotherapy and poly-(ADP-ribose) polymerase (PARP) inhibitors. However, growing evidence suggests that BRCA1- and BRCA2-associated OCs display distinct characteristics, most notably in long-term patient survival...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28540598/parp-inhibitors-in-prostate-cancer
#16
REVIEW
Praveen Ramakrishnan Geethakumari, Matthew J Schiewer, Karen E Knudsen, Wm Kevin Kelly
The genomic landscape of metastatic prostate cancer (mPCa) reveals that up to 90% of patients harbor actionable mutations and >20% have somatic DNA repair gene defects (DRD). This provides the therapeutic rationale of PARP inhibition (PARPi) to achieve "synthetic lethality" in treating this fatal disease. Clinical trials with PARP inhibitors have shown significant response rates up to 88% for PCa patients having DRD like BRCA1/2 or ATM mutations. The FDA has awarded "breakthrough designation" to develop the PARPi olaparib in treating this subset of metastatic PCa patients...
June 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28536297/androgen-receptor-inhibitor-induced-brcaness-and-parp-inhibition-are-synthetically-lethal-for-castration-resistant-prostate-cancer
#17
Likun Li, Styliani Karanika, Guang Yang, Jiangxiang Wang, Sanghee Park, Bradley M Broom, Ganiraju C Manyam, Wenhui Wu, Yong Luo, Spyridon Basourakos, Jian H Song, Gary E Gallick, Theodoros Karantanos, Dimitrios Korentzelos, Abul Kalam Azad, Jeri Kim, Paul G Corn, Ana M Aparicio, Christopher J Logothetis, Patricia Troncoso, Timothy Heffernan, Carlo Toniatti, Hyun-Sung Lee, Ju-Seog Lee, Xuemei Zuo, Wenjun Chang, Jianhua Yin, Timothy C Thompson
Cancers with loss-of-function mutations in BRCA1 or BRCA2 are deficient in the DNA damage repair pathway called homologous recombination (HR), rendering these cancers exquisitely vulnerable to poly(ADP-ribose) polymerase (PARP) inhibitors. This functional state and therapeutic sensitivity is referred to as "BRCAness" and is most commonly associated with some breast cancer types. Pharmaceutical induction of BRCAness could expand the use of PARP inhibitors to other tumor types. For example, BRCA mutations are present in only ~20% of prostate cancer patients...
May 23, 2017: Science Signaling
https://www.readbyqxmd.com/read/28507103/nicotinic-acid-phosphoribosyltransferase-regulates-cancer-cell-metabolism-susceptibility-to-nampt-inhibitors-and-dna-repair
#18
Francesco Piacente, Irene Caffa, Silvia Ravera, Giovanna Sociali, Mario Passalacqua, Valerio G Vellone, Pamela Becherini, Daniele Reverberi, Fiammetta Monacelli, Alberto Ballestrero, Patrizio Odetti, Antonia Cagnetta, Michele Cea, Aimable Nahimana, Michel Duchosal, Santina Bruzzone, Alessio Nencioni
In the last decade, substantial efforts have been made to identify NAD(+) biosynthesis inhibitors, specifically against nicotinamide phosphoribosyltransferase (NAMPT), as preclinical studies indicate their potential efficacy as cancer drugs. However, the clinical activity of NAMPT inhibitors has proven limited, suggesting that alternative NAD(+) production routes exploited by tumors confer resistance. Here, we show the gene encoding nicotinic acid phosphoribosyltransferase (NAPRT), a second NAD(+)-producing enzyme, is amplified and overexpressed in a subset of common types of cancer, including ovarian cancer, where NAPRT expression correlates with a BRCAness gene expression signature...
July 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28494179/predictive-biomarkers-for-triple-negative-breast-cancer-treated-with-platinum-based-chemotherapy
#19
Juan Jin, Wenwen Zhang, Wenfei Ji, Fang Yang, Xiaoxiang Guan
Treatment of triple negative breast cancer (TNBC) has been a big challenge since it is defined. To date, platinum-based chemotherapy has played a significant role in the treatment of TNBC patients. However, some patients do not respond to platinum salts or gradually develop chemoresistance, resulting in little effect, or even some adverse effects. Here, we review numerous preclinical and clinical investigations to summarize possible mechanisms and potential predictive biomarkers of platinum in TNBC. The homologous recombination deficiency (HRD) resulting from the loss of BRCA function is the main rationale of platinum efficacy in TNBC...
June 3, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28466156/mirna-regulation-is-important-for-dna-damage-repair-and-recognition-in-malignant-pleural-mesothelioma
#20
Fabian Dominik Mairinger, Robert Werner, Elena Flom, Jan Schmeller, Sabrina Borchert, Michael Wessolly, Jeremias Wohlschlaeger, Thomas Hager, Thomas Mairinger, Jens Kollmeier, Daniel Christian Christoph, Kurt Werner Schmid, Robert Fred Henry Walter
Platin-containing regimes are currently considered as state-of-the-art therapies in malignant pleural mesotheliomas (MPM) but show dissatisfying response rates ranging from 6 to 16% only. Still, the reasons for the rather poor efficacy remain largely unknown. A clear stratification of patients based on new biomarkers seems to be a promising approach to enhance clinical management, which would be a long-needed improvement for MPM patients but does not seem likely soon unless new biomarkers can be validated. Twenty-four formalin-fixed, paraffin-embedded (FFPE) tumour specimens were subjected to a miRNA expression screening of 800 important miRNAs using digital quantification via the nCounter technique (NanoString)...
June 2017: Virchows Archiv: An International Journal of Pathology
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