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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
#1
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
#2
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
#3
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
#4
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
#5
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...
2016: Journal of Translational Medicine
https://www.readbyqxmd.com/read/27630665/post-transcriptional-regulation-of-brca2-through-interactions-with-mir-19a-and-mir-19b
#6
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
#7
Esther H Lips, Rashmie 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 (ER)-positive breast cancer in BRCA1 mutation carriers arises at an older age with less aggressive tumor characteristics than ER negative 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 non-functioning 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
#8
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
#9
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
#10
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
#11
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
#12
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...
June 29, 2016: International Journal of Gynecological Pathology
https://www.readbyqxmd.com/read/27328445/germline-mutations-in-dna-repair-genes-may-predict-neoadjuvant-therapy-response-in-triple-negative-breast-patients
#13
Laura Spugnesi, Michele Gabriele, Rosa Scarpitta, Mariella Tancredi, Luisa Maresca, Gaetana Gambino, Anita Collavoli, Paolo Aretini, Ilaria Bertolini, Barbara Salvadori, Elisabetta Landucci, Andrea Fontana, Elena Rossetti, Manuela Roncella, Giuseppe Antonio Naccarato, Maria Adelaide Caligo
Triple negative breast cancers (TNBCs) represent about 15-20% of all breast cancer cases and are characterized by a complex molecular heterogeneity. Some TNBCs exhibit clinical and pathological properties similar to BRCA-mutated tumors, without actually bearing a mutation in BRCA genes. This "BRCAness" phenotype may be explained by germline mutations in other genes involved in DNA repair. Although respond to chemotherapy with alkylating agents, they have a high risk of recurrence and progression. Some studies have shown the efficacy of neoadjuvant therapy in TNBC patients with DNA repair defects, but proper biomarkers of DNA repair deficiency are still needed...
December 2016: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/27317574/dna-repair-deficiency-is-common-in-advanced-prostate-cancer-new-therapeutic-opportunities
#14
REVIEW
Mallika Dhawan, Charles J Ryan, Alan Ashworth
UNLABELLED: : Advances in DNA sequencing technology have created a wealth of information regarding the genomic landscape of prostate cancer. It had been thought that BRCA1 and BRCA2 mutations were associated with only a small fraction of prostate cancer cases. However, recent genomic analysis has revealed that germline or somatic inactivating mutations in BRCA1 or BRCA2, or other genes involved in the homologous recombination (HR) pathway of DNA repair collectively occur in as much as 20%-25% of advanced prostate cancers...
August 2016: Oncologist
https://www.readbyqxmd.com/read/27249731/gynecologic-cancers-emerging-novel-strategies-for-targeting-dna-repair-deficiency
#15
Rebecca S Kristeleit, Rowan E Miller, Elise C Kohn
The presence of a BRCA mutation, somatic or germline, is now established as a standard of care for selecting patients with ovarian cancer for treatment with a PARP inhibitor. During the clinical development of the PARP inhibitor class of agents, a subset of women without BRCA mutations were shown to respond to these drugs (termed "BRCAness"). It was hypothesized that other genetic abnormalities causing a homologous recombinant deficiency (HRD) were sensitizing the BRCA wild-type cancers to PARP inhibition. The molecular basis for these other causes of HRD are being defined...
2016: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/27226207/evaluation-of-the-methods-to-identify-patients-who-may-benefit-from-parp-inhibitor-use
#16
REVIEW
Diana Lim, Joanne Ngeow
The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in treating cancers associated with BRCA1/2 mutations hinges upon the concept of synthetic lethality and exemplifies the principles of precision medicine. Currently, most clinical trials are recruiting patients based on pathological subtypes or have included BRCA mutation analysis (germ line and/or somatic) as part of the selection criteria. Mounting evidence, however, suggests that these drugs may also be efficacious in tumors with defects in other genes involved in the homologous recombination repair pathway...
June 2016: Endocrine-related Cancer
https://www.readbyqxmd.com/read/27184417/triple-negative-breast-cancer-challenges-and-opportunities-of-a-heterogeneous-disease
#17
Giampaolo Bianchini, Justin M Balko, Ingrid A Mayer, Melinda E Sanders, Luca Gianni
Chemotherapy is the primary established systemic treatment for patients with triple-negative breast cancer (TNBC) in both the early and advanced-stages of the disease. The lack of targeted therapies and the poor prognosis of patients with TNBC have fostered a major effort to discover actionable molecular targets to treat patients with these tumours. Massively parallel sequencing and other 'omics' technologies have revealed an unexpected level of heterogeneity of TNBCs and have led to the identification of potentially actionable molecular features in some TNBCs, such as germline BRCA1/2 mutations or 'BRCAness', the presence of the androgen receptor, and several rare genomic alterations...
November 2016: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/27041672/brcaness-is-beneficial-for-indicating-triple-negative-breast-cancer-patients-resistant-to-taxane
#18
T Ishikawa, K Narui, M Tanabe, K Kida, M S Oba, A Yamada, Y Ichikawa, I Endo
AIM: Triple negative breast cancer (TNBC) is a heterogeneous disease and is associated with the cancer stem cell (CSC), basal-like, and BRCA1 function deficient (BRCAness) subtypes. We examined these 3 subtypes in TNBC and compared their chemosensitivity against anthracycline or taxane with a special attention to BRCAness. METHODS: Sixty-six TNBC cases were obtained from a randomized phase II trial comparing TCx6 (TC6) with FEC-Docetaxel (FEC-D) as neoadjuvant chemotherapy...
July 2016: European Journal of Surgical Oncology
https://www.readbyqxmd.com/read/27016230/copy-number-deletion-of-rad50-as-predictive-marker-of-brcaness-and-parp-inhibitor-response-in-brca-wild-type-ovarian-cancer
#19
Min Zhang, Guoyan Liu, Fengxia Xue, Robert Edwards, Anil K Sood, Wei Zhang, Da Yang
OBJECTIVE: To identify novel prognostic and therapeutic markers for PARP inhibitors in BRCA wild type ovarian cancer (OvCa). METHODS: BRCAness status was defined by analyzing whole-exome deep sequencing data from 220 BRCAwt OvCa cases in TCGA. Thirty-three DNA-repair genes were screened in an integrated manner for BRCA-independent mechanism of BRCAness using multiple-dimensional genomic data. Publicly available databases and siRNA knock-down were used for external validation and evaluation of drug response in OvCa cell lines...
April 2016: Gynecologic Oncology
https://www.readbyqxmd.com/read/26979459/different-array-cgh-profiles-within-hereditary-breast-cancer-tumors-associated-to-brca1-expression-and-overall-survival
#20
Carolina Alvarez, Andrés Aravena, Teresa Tapia, Ester Rozenblum, Luisa Solís, Alejandro Corvalán, Mauricio Camus, Manuel Alvarez, David Munroe, Alejandro Maass, Pilar Carvallo
BACKGROUND: Array CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease...
March 15, 2016: BMC Cancer
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