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BRCAness

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https://www.readbyqxmd.com/read/28159920/tgfbeta-and-mirna-regulation-in-familial-and-sporadic-breast-cancer
#1
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...
January 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28148839/2-hydroxyglutarate-produced-by-neomorphic-idh-mutations-suppresses-homologous-recombination-and-induces-parp-inhibitor-sensitivity
#2
Parker L Sulkowski, Christopher D Corso, Nathaniel D Robinson, Susan E Scanlon, Karin R Purshouse, Hanwen Bai, Yanfeng Liu, Ranjini K Sundaram, Denise C Hegan, Nathan R Fons, Gregory A Breuer, Yuanbin Song, Ketu Mishra-Gorur, Henk M De Feyter, Robin A de Graaf, Yulia V Surovtseva, Maureen Kachman, Stephanie Halene, Murat Günel, Peter M Glazer, Ranjit S Bindra
2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors...
February 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28101677/emesis-and-nausea-related-to-single-agent-trabectedin-in-ovarian-cancer-patients-a-sub-study-of-the-mito15-project
#3
Marilena Di Napoli, Chiara Della Pepa, Laura Arenare, Giovanni Scambia, Domenica Lorusso, Francesco Raspagliesi, Gabriella Ferrandina, Vanda Salutari, Roberto Sorio, Anna Maria Mosconi, Giorgia Mangili, Lucia Borgato, Stefano Lepori, Angela Salvino, Sandro Pignata, Sabrina Chiara Cecere
The MITO 15 was a prospective, single-arm trial, evaluating trabectedin monotherapy in patients with recurrent ovarian cancer (OC) who were BRCA mutation-carriers or had a BRCAness phenotype. It is largely reported that trabectedin may induce nausea and vomiting but the real emetogenic potential of the drug, in the different schedules, has never been fully described; furthermore, OC patients are known to have an enhanced risk of developing nausea and vomiting due to female gender, abdominal spreading of the disease, and major surgery experienced by most of them...
January 19, 2017: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
https://www.readbyqxmd.com/read/28099152/the-emsy-threonine-207-phospho-site-is-required-for-emsydriven-suppression-of-dna-damage-repair
#4
Petar Jelinic, Laura A Eccles, Jill Tseng, Paulina Cybulska, Monicka Wielgos, Simon N Powell, Douglas A Levine
BRCA1 and BRCA2 are essential for the repair of double-strand DNA breaks, and alterations in these genes are a hallmark of breast and ovarian carcinomas. Other functionally related genes may also play important roles in carcinogenesis. Amplification of EMSY, a putative BRCAness gene, has been suggested to impair DNA damage repair by suppressing BRCA2 function. We employed direct repeat GFP (DR-GFP) and RAD51 foci formation assays to show that EMSY overexpression impairs the repair of damaged DNA, suggesting that EMSY belongs to the family of BRCAness proteins...
January 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/27978798/combination-platinum-based-and-dna-damage-response-targeting-cancer-therapy-evolution-and-future-directions
#5
Spyridon P Basourakos, Likun Li, Ana M Aparicio, Paul G Corn, Jeri Kim, Timothy C Thompson
Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Alkylating factors, i.e., interstrand crosslinking (ICL) agents, including platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR) including DNA repair, and mainly involves the nucleotide excision repair (NER) pathway. When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis...
December 14, 2016: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/27943283/prophylactic-window-therapy-with-the-clinical-poly-adp-ribose-polymerase-inhibitor-olaparib-delays-brca1-deficient-mammary-tumour-formation-in-mice
#6
Marieke van de Ven, Eline van der Burg, Hanneke van der Gulden, Sjoerd Klarenbeek, Peter Bouwman, Jos Jonkers
Women with heterozygous germline mutations in the BRCA1 tumour suppressor gene are strongly predisposed to developing early-onset breast cancer through loss of the remaining wild-type BRCA1 allele and inactivation of TP53. Although tumour prevention strategies in BRCA1-mutation carriers are still limited to prophylactic surgery, several therapeutic strategies have been developed to target the DNA repair defects (also known as 'BRCAness') of BRCA1-deficient tumours. In particular, DNA-damaging agents such as platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors show strong activity against BRCA1-mutated tumours...
December 9, 2016: Journal of Pathology
https://www.readbyqxmd.com/read/27943282/brca1-2-negative-hereditary-triple-negative-breast-cancers-exhibit-brcaness
#7
Pawel Domagala, Jolanta Hybiak, Cezary Cybulski, Jan Lubinski
BRCA1/2-associated breast cancers are sensitive to poly(ADPribose) polymerase (PARP) inhibitors and platinum compounds mainly due to their deficiency in DNA repair via homologous recombination (HR). However, approximately only 15% of triple-negative breast cancers (TNBCs) are BRCA1/2-associated. TNBCs that exhibit BRCAness (a phenotype reflecting impaired HR in BRCA1/2-negative tumors) are also regarded sensitive to PARP inhibitors and platinum compounds. Thus, we hypothesized that hereditary BRCA1/2-negative TNBCs may exhibit BRCAness...
April 1, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27935989/brcaness-and-prognosis-in-triple-negative-breast-cancer-patients-treated-with-neoadjuvant-chemotherapy
#8
Hirokazu Tanino, Yoshimasa Kosaka, Hiroshi Nishimiya, Youko Tanaka, Naoko Minatani, Mariko Kikuchi, Akiko Shida, Mina Waraya, Hiroshi Katoh, Takumo Enomoto, Norihiko Sengoku, Sabine Kajita, Robert M Hoffman, Masahiko Watanabe
BRCAness is defined as the set of traits in which BRCA1 dysfunction, arising from gene mutation, methylation or deletion, results in DNA repair deficiency. In the present study, we addressed BRCAness, therapeutic efficacy, recurrence, and survival in patients with triple negative breast cancer (TNBC) who were treated with neoadjuvant chemotherapy at Kitasato University Hospital, Japan, between April 2006 and October 2012. BRCAness was determined by preoperative core needle biopsy (CNB) specimens and surgical specimens...
2016: PloS One
https://www.readbyqxmd.com/read/27884198/use-of-poly-adp-ribose-polymerase-parp-inhibitors-in-cancer-cells-bearing-ddr-defects-the-rationale-for-their-inclusion-in-the-clinic
#9
REVIEW
Aniello Cerrato, Francesco Morra, Angela Celetti
BACKGROUND: DNA damage response (DDR) defects imply genomic instability and favor tumor progression but make the cells vulnerable to the pharmacological inhibition of the DNA repairing enzymes. Targeting cellular proteins like PARPs, which cooperate and complement molecular defects of the DDR process, induces a specific lethality in DDR defective cancer cells and represents an anti-cancer strategy. Normal cells can tolerate the DNA damage generated by PARP inhibition because of an efficient homologous recombination mechanism (HR); in contrast, cancer cells with a deficient HR are unable to manage the DSBs and appear especially sensitive to the PARP inhibitors (PARPi) effects...
November 24, 2016: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/27869446/-oncopathological-aspects-of-brca1-and-brca2-genes-inactivation-in-tumors-of-ovary-fallopian-tube-and-pelvic-peritoneum
#10
Petr Škapa, Pavel Dundr
Ovarian carcinoma represents a heterogeneous group of malignant epithelial tumors which could be divided into two fundamental groups: Type I (endometrioid carcinoma, clear cell carcinoma, low grade serous carcinoma, mucinous carcinoma and more rare seromucinous carcinoma and malignant Brenner tumor) and type II (high grade serous carcinoma - HGSC). HGSC is the most frequent ovarian carcinoma which may be etiologically linked to inactivation of tumor suppressor genes BRCA1/2 and TP53 and differs from type I carcinomas by higher aggressiveness, tendency to peritoneal spread and worse prognosis...
2016: Ceskoslovenská Patologie
https://www.readbyqxmd.com/read/27869444/-brca1-and-brca2-pathologists-starting-kit
#11
Petr Škapa
Dysfunction of tumor suppressor genes BRCA1 and BRCA2 is involved in the pathogenesis of malignant tumors, especially breast and ovarian carcinoma. BRCA1/2 genes may be inactivated by germinal and somatic mutations or epigenetic changes. Germinal mutations are responsible for the hereditary breast and ovarian carcinoma syndrome. Defects of BRCA1/2 genes lead to the failure of homologous recombination, the basic mechanism for DNA double strand break repair. The resultant genomic instability is associated with a high risk of malignant transformation of the cell, but it also results in a higher sensitivity of tumors to platinum-based chemotherapeutic compounds which damage DNA structure directly...
2016: Ceskoslovenská Patologie
https://www.readbyqxmd.com/read/27673289/the-status-of-poly-adenosine-diphosphate-ribose-polymerase-parp-inhibitors-in-ovarian-cancer-part-2-extending-the-scope-beyond-olaparib-and-brca1-2-mutations
#12
REVIEW
Rowan E Miller, Jonathan A Ledermann
Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown clinical activity in epithelial ovarian cancer, leading both the US Food and Drug Administration (FDA) and the European Medicines Agency to approve olaparib for tumors characterized by BRCA1 and BRCA2 mutations. However, it is becoming increasingly evident that tumors that share molecular features with BRCA-mutant tumors-a concept known as BRCAness-also may exhibit defective homologous recombination DNA repair, and therefore will respond to PARP inhibition...
September 2016: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/27634150/update-on-poly-adp-ribose-polymerase-inhibition-for-ovarian-cancer-treatment
#13
REVIEW
Anselmo Papa, Davide Caruso, Martina Strudel, Silverio Tomao, Federica Tomao
BACKGROUND: Despite standard treatment for epithelial ovarian cancer (EOC), that involves cytoreductive surgery followed by platinum-based chemotherapy, and initial high response rates to these, up to 80 % of patients experience relapses with a median progression-free survival of 12-18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and Poly(ADP-ribose) polymerase (PARP) inhibitors...
September 15, 2016: Journal of Translational Medicine
https://www.readbyqxmd.com/read/27630665/post-transcriptional-regulation-of-brca2-through-interactions-with-mir-19a-and-mir-19b
#14
Elena Mogilyansky, Peter Clark, Kevin Quann, Honglei Zhou, Eric Londin, Yi Jing, Isidore Rigoutsos
Breast cancer type 2, early onset susceptibility gene (BRCA2) is a major component of the homologous recombination DNA repair pathway. It acts as a tumor suppressor whose function is often lost in cancers. Patients with specific mutations in the BRCA2 gene often display discrete clinical, histopathological, and molecular features. However, a subset of sporadic cancers has wild type BRCA2 and display defects in the homology-directed repair pathway, which is the hallmark of 'BRCAness.' The mechanisms by which BRCAness arises are not well understood but post-transcriptional regulation of BRCA2 gene expression by microRNAs (miRNAs) may contribute to this phenotype...
2016: Frontiers in Genetics
https://www.readbyqxmd.com/read/27620280/brca1-mutated-estrogen-receptor-positive-breast-cancer-shows-brcaness-suggesting-sensitivity-to-drugs-targeting-homologous-recombination-deficiency
#15
Esther H Lips, Rashmie D Debipersad, Caroline E Scheerman, Lennart Mulder, Gabe S Sonke, Lizet E van der Kolk, Jelle Wesseling, Frans B L Hogervorst, Petra M Nederlof
Purpose: As estrogen receptor-positive (ER(+)) breast cancer in BRCA1 mutation carriers arises at an older age with less aggressive tumor characteristics than ER-negative (ER(-)) BRCA1-mutated breast cancer, it has been suggested that these tumors are "sporadic" and not BRCA1 driven. With the introduction of targeted treatments specific for tumors with a nonfunctioning BRCA1 or BRCA2 gene, the question whether the BRCA genes are impaired in the tumor is highly relevant. Therefore, we performed genomic profiling of BRCA1-mutated ER(+) tumors...
September 12, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27561088/association-of-the-germline-brca2-missense-variation-glu2663lys-with-high-sensitivity-to-trabectedin-based-treatment-in-soft-tissue-sarcoma
#16
Gianmaria Miolo, Alessandra Viel, Vincenzo Canzonieri, Tania Baresic, Angela Buonadonna, Davide Adriano Santeufemia, Della Puppa Lara, Giuseppe Corona
We report an interesting clinical case of a patient carrying a specific BRCA2 germline variant affected by bone and hepatic metastases from a high grade uterine stromal sarcoma who obtained a complete metabolic response after only 3 cycles of trabectedin treatment (1.5 mg/m(2) given intravenously over 24 hours every 21 days). Molecular investigations linked this outstanding positive pharmacological response with the loss of heterozygosity (LOH) of the mutated BRCA2 gene. These data support the hypothesis that the response to trabectedin may be positively conditioned by the different DNA repair defects present in the neoplasm and that BRCAness tumor genotype is important in determining the efficacy of trabectedin-based chemotherapy...
October 2, 2016: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/27447864/osteosarcoma-cells-with-genetic-signatures-of-brcaness-are-susceptible-to-the-parp-inhibitor-talazoparib-alone-or-in-combination-with-chemotherapeutics
#17
Florian Engert, Michal Kovac, Daniel Baumhoer, Michaela Nathrath, Simone Fulda
We recently discovered mutation signatures reminiscent of BRCA deficiency in the vast majority of a set of primary osteosarcomas (OS). In the current study, we therefore investigated the sensitivity of a panel of OS cell lines to the poly(ADP)-ribose polymerase (PARP) inhibitor talazoparib alone and in combination with several chemotherapeutic drugs (i.e. temozolomide (TMZ), SN-38, doxorubicin, cisplatin, methotrexate (MTX), etoposide/carboplatin). Here, we identified an association between homologous recombination (HR) repair deficiency and the response of OS cell lines to talazoparib...
July 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27401886/biology-and-management-of-patients-with-triple-negative-breast-cancer
#18
REVIEW
Priyanka Sharma
UNLABELLED: : Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancers and is associated with poor long-term outcomes compared with other breast cancer subtypes. Because of the lack of approved targeted therapy, at present chemotherapy remains the mainstay of treatment for early and advanced disease. TNBC is enriched for germline BRCA mutation, providing a foundation for the use of this as a biomarker to identify patients suitable for treatment with DNA-damaging agents...
September 2016: Oncologist
https://www.readbyqxmd.com/read/27385001/mir-151-5p-targeting-chromatin-remodeler-smarca5-as-a-marker-for-the-brcaness-phenotype
#19
Stefania Tommasi, Rosamaria Pinto, Katia Danza, Brunella Pilato, Orazio Palumbo, Lucia Micale, Simona De Summa
In recent years, the assessment of biomarkers useful for "precision medicine" has been a hot topic in research. The involvement of microRNAs in the pathogenesis of breast cancer has been highly investigated with the aim of being able to molecularly stratify this highly heterogeneous disease. Our aim was to identify microRNAs targeting DNA repair machinery, through Affymetrix GeneChip miRNA Arrays, in a cohort of BRCA-related and sporadic breast cancers. Moreover, we analyzed microRNA expression taking into account our previous results on the expression of PARP1, because of its importance in targeted therapy...
June 30, 2016: Oncotarget
https://www.readbyqxmd.com/read/27362900/the-prognostic-value-of-brca1-and-parp-expression-in-epithelial-ovarian-carcinoma-immunohistochemical-detection
#20
Mette Hjortkjær, Marianne Waldstrøm, Anders Jakobsen, Hanne Kanstrup, Erik Søgaard-Andersen, Karina Dahl Steffensen
BRCA1/2 mutation status in epithelial ovarian cancer (EOC) presently relies on genetic testing which is resource consuming. Immunohistochemistry is cheap, fairly reproducible, and may identify gene product alterations due to both germline and somatic mutations and other defects along the BRCA gene pathway (BRCAness phenomenon), which is important when treatment with poly (adenosine-diphosphate-ribose) polymerase (PARP) inhibitors is considered. The aim of this study was to investigate immunohistochemical detection of BRCA1 and PARP expression in EOC and their possible prognostic relevance...
March 2017: International Journal of Gynecological Pathology
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