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BRCA mutations

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https://www.readbyqxmd.com/read/28339459/functional-classification-of-dna-variants-by-hybrid-minigenes-identification-of-30-spliceogenic-variants-of-brca2-exons-17-and-18
#1
Eugenia Fraile-Bethencourt, Beatriz Díez-Gómez, Valeria Velásquez-Zapata, Alberto Acedo, David J Sanz, Eladio A Velasco
Mutation screening of the breast cancer genes BRCA1 and BRCA2 identifies a large fraction of variants of uncertain clinical significance (VUS) whose functional and clinical interpretations pose a challenge for genomic medicine. Likewise, an increasing amount of evidence indicates that genetic variants can have deleterious effects on pre-mRNA splicing. Our goal was to investigate the impact on splicing of a set of reported variants of BRCA2 exons 17 and 18 to assess their role in hereditary breast cancer and to identify critical regulatory elements that may constitute hotspots for spliceogenic variants...
March 24, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28327944/a-phase-2-randomized-double-blind-placebo-%C3%A2-controlled-study-of-chemo-immunotherapy-combination-using-motolimod-with-pegylated-liposomal-doxorubicin-in-recurrent-or-persistent-ovarian-cancer-a-gynecologic-oncology-group-partners-study
#2
B J Monk, M F Brady, C Aghajanian, H A Lankes, T Rizack, J Leach, J M Fowler, R Higgins, P Hanjani, M Morgan, R Edwards, W Bradley, T Kolevska, P Foukas, E Swisher, K S Anderson, R Gottardo, J K Bryan, M Newkirk, K L Manjarrez, R S Mannel, R M Hershberg, G Coukos
Background: A phase 2, randomized, placebo-controlled trial was conducted in women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and safety of motolimod-a Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses-combined with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death. Patients and methods: Women with ovarian, fallopian tube, or primary peritoneal carcinoma were randomized 1 : 1 to receive PLD in combination with blinded motolimod or placebo...
February 21, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28322442/systems-analysis-of-dynamic-transcription-factor-activity-identifies-targets-for-treatment-in-olaparib-resistant-cancer-cells
#3
Joseph T Decker, Eric C Hobson, Yining Zhang, Seungjin Shin, Alexandra L Thomas, Jacqueline S Jeruss, Kelly B Arnold, Lonnie D Shea
The development of resistance to targeted therapeutics is a challenging issue for the treatment of cancer. Cancers that have mutations in BRCA, a DNA repair protein, have been treated with poly (ADP-ribose) polymerase (PARP) inhibitors, which target a second DNA repair mechanism with the aim of inducing synthetic lethality. While these inhibitors have shown promise clinically, the development of resistance can limit their effectiveness as a therapy. This study investigated mechanisms of resistance in BRCA-mutated cancer cells (HCC1937) to Olaparib (AZD2281) using TRACER, a technique for measuring dynamics of transcription factor (TF) activity in living cells...
March 21, 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28320467/the-effect-of-hormone-therapy-on-quality-of-life-and-breast-cancer-risk-after-risk-reducing-salpingo-oophorectomy-a-systematic-review
#4
Tasneem Siyam, Sue Ross, Sandra Campbell, Dean T Eurich, Nesé Yuksel
BACKGROUND: It is unclear if the use of hormone therapy (HT) in carriers of BRCA mutations improves the quality of life (QOL) without increasing the risk of breast cancer following a risk-reducing salpingo-oophorectomy (RRSO). Our objective was to assess the effect of HT on QOL and breast cancer risk, after RRSO. METHODS: We searched MEDLINE, EMBASE, CINHAL, and others, from inception to July 22, 2016, to identify relevant studies. Two reviewers independently screened identified records for controlled trials and observational studies that addressed the effect of HT on QOL and breast cancer risk in women with BRCA mutations, post RRSO...
March 21, 2017: BMC Women's Health
https://www.readbyqxmd.com/read/28319063/compromised-brca1-palb2-interaction-is-associated-with-breast-cancer-risk
#5
T K Foo, M Tischkowitz, S Simhadri, T Boshari, N Zayed, K A Burke, S H Berman, P Blecua, N Riaz, Y Huo, Y C Ding, S L Neuhausen, B Weigelt, J S Reis-Filho, W D Foulkes, B Xia
The major breast cancer suppressor proteins BRCA1 and BRCA2 play essential roles in homologous recombination (HR)-mediated DNA repair, which is thought to be critical for tumor suppression. The two BRCA proteins are linked by a third tumor suppressor, PALB2, in the HR pathway. While truncating mutations in these genes are generally pathogenic, interpretation of missense variants remains a challenge. To date, patient-derived missense variants that disrupt PALB2 binding have been identified in BRCA1 and BRCA2; however, there has not been sufficient evidence to prove their pathogenicity in humans, and no variants in PALB2 that disrupt either its BRCA1 or BRCA2 binding have been reported...
March 20, 2017: Oncogene
https://www.readbyqxmd.com/read/28316110/proteasome-ubiquitin-receptor-psmd4-is-an-amplification-target-in-breast-cancer-and-may-predict-sensitivity-to-parpi
#6
Marlena S Fejzo, Lee Anderson, Hsiao-Wang Chen, Enrique Guandique, Ondrej Kalous, Dylan Conklin, Dennis J Slamon
Poly(ADP-ribose) polymerase 1 (PARP1) is an enzyme involved in DNA repair under investigation as a chemotherapeutic target. Current randomized phase 3 trials of PARPi in metastatic breast cancer are limited to patients with documented BRCA1/2 mutations and no biomarker of PARPi beyond BRCA status is available. In an effort to identify novel biomarkers for PARP inihibition, we created a cell line (HCC1187/TALRES) resistant to the PARP1 inhibitor talazoparib. Herein we show by array-CGH that HCC1187/TALRES has a selective loss of the proteasome ubiquitin receptor PSMD4 amplicon resulting in significant down-regulation of PSMD4...
March 18, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28314837/risk-reducing-strategies-for-ovarian-cancer-in-brca-mutation-carriers-a-balancing-act
#7
Roi Tschernichovsky, Annekathryn Goodman
OBJECTIVE: The objective of this study was to review the role of bilateral salpingo-oophorectomy in BRCA mutation (mBRCA) carriers and alternative interventions in risk reduction of ovarian cancer (OC). MATERIALS AND METHODS: A systematic review using PubMed, MEDLINE, EMBASE, and the Cochrane library was conducted to identify studies of different strategies to prevent OC in mBRCA carriers, including bilateral salpingo-oophorectomy, prophylactic salpingectomy with delayed oophorectomy, intensive surveillance, and chemoprevention...
March 17, 2017: Oncologist
https://www.readbyqxmd.com/read/28314588/risk-of-breast-cancer-after-a-diagnosis-of-ovarian-cancer-in-brca-mutation-carriers-is-preventive-mastectomy-warranted
#8
Jacob McGee, Vasily Giannakeas, Beth Karlan, Jan Lubinski, Jacek Gronwald, Barry Rosen, John McLaughlin, Harvey Risch, Ping Sun, William D Foulkes, Susan L Neuhausen, Joanne Kotsopoulos, Steven A Narod
OBJECTIVE: Preventive breast surgery and MRI screening are offered to unaffected BRCA mutation carriers. The clinical benefit of these two modalities has not been evaluated among mutation carriers with a history of ovarian cancer. Thus, we sought to determine whether or not BRCA mutation carriers with ovarian cancer would benefit from preventive mastectomy or from MRI screening. METHODS: First, the annual mortality rate for ovarian cancer patients was estimated for a cohort of 178 BRCA mutation carriers from Ontario, Canada...
March 14, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28299592/the-effect-of-a-celebrity-health-disclosure-on-demand-for-health-care-trends-in-brca-testing-and-subsequent-health-services-use
#9
Megan C Roberts, Stacie B Dusetzina
In May 2013, an internationally renowned celebrity-Angelina Jolie-disclosed her receipt of BRCA1/BRCA2 (BRCA) testing and subsequent double mastectomy in a highly publicized editorial. Publicity surrounding celebrity health services use increases awareness of important health issues and demand for health services. We aimed to describe BRCA testing trends before and after Jolie's disclosure, breast cancer-related services use following testing, and test reimbursement trends. MarketScan Commercial Claims data were used to compare trends in BRCA testing before and after Jolie's health disclosure using an interrupted time series model among women aged 18-64...
March 15, 2017: Journal of Community Genetics
https://www.readbyqxmd.com/read/28294317/the-spectrum-of-brca-mutations-and-characteristics-of-brca-associated-breast-cancers-in-china-screening-of-2991-patients-and-1043-controls-by-next-generation-sequencing
#10
Guan-Tian Lang, Jin-Xiu Shi, Xin Hu, Chen-Hui Zhang, Ling Shan, Chuan-Gui Song, Zhi-Gang Zhuang, A-Yong Cao, Hong Ling, Ke-Da Yu, Li Shan, Meng-Hong Sun, Xiao-Yan Zhou, Wei Huang, Zhi-Ming Shao
To characterize the prevalence of BRCA mutations and characteristics of BRCA carriers in China and to update the clinical recommendations for BRCA testing, we conducted a wide screen for BRCA mutations using next-generation sequencing (NGS). A total of 4,034 Chinese subjects were screened for germline BRCA1/2 mutations, including 2,991 breast cancer patients and 1,043 healthy individuals from the community enrolled as controls. We developed an NGS-based approach to perform BRCA1/2 screening. BRCA mutations were identified in 9...
March 14, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28291131/study-of-selected-brca1-brca2-and-pik3ca-mutations-in-benign-and-malignant-lesions-of-anogenital-mammary-like-glands
#11
Anastasia M Konstantinova, Ksenya V Shelekhova, Evgeny N Imyanitov, Aglaya Iyevleva, Denisa Kacerovska, Michal Michal, Dmitry V Kazakov
Anogenital mammary-like glands (AGMLGs) are nowadays considered a normal component of the anogenital area. Lesions involving AGMLGs are histopathologically very similar to their mammary counterparts, but the information on molecular biological mechanisms in these vulvar/perianal tumors is scarce. Mutations in the PI3K-AKT cascade have been found in hidradenoma papilliferum. The authors studied selected BRCA1, BRCA2, and PIK3CA mutations in series of benign and malignant neoplasms thought to be associated with AGMLGs, including 9 cases of primary extramammary Paget disease, 3 different cases of mammary-type carcinoma (adenoid cystic like, tubulolobular, and invasive ductal like), and 5 cases of hidradenoma papilliferum...
March 9, 2017: American Journal of Dermatopathology
https://www.readbyqxmd.com/read/28280302/defective-dna-repair-mechanisms-in-prostate-cancer-impact-of-olaparib
#12
REVIEW
Francesca De Felice, Vincenzo Tombolini, Francesco Marampon, Angela Musella, Claudia Marchetti
The field of prostate oncology has continued to change dramatically. It has truly become a field that is intensely linked to molecular genetic alterations, especially DNA-repair defects. Germline breast cancer 1 gene (BRCA1) and breast cancer 2 gene (BRCA2) mutations are implicated in the highest risk of prostate cancer (PC) predisposition and aggressiveness. Poly adenosine diphosphate ribose polymerase (PARP) proteins play a key role in DNA repair mechanisms and represent a valid target for new therapies. Olaparib is an oral PARP inhibitor that blocks DNA repair pathway and coupled with BRCA mutated-disease results in tumor cell death...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28277317/brca1-2-germline-missense-mutations-a-systematic-review
#13
Giovanni Corso, Irene Feroce, Mattia Intra, Antonio Toesca, Francesca Magnoni, Manuela Sargenti, Paola Naninato, Pietro Caldarella, Gianmatteo Pagani, Annarita Vento, Paolo Veronesi, Bernardo Bonanni, Viviana Galimberti
Hereditary breast and ovarian cancer is an inherited syndrome associated with BRCA1/2 germline defects. The identified mutations are classified as missense, large deletion, insertion, nonsense and splice-site variants with a deleterious impact on BRCA1/2 function. Part of these forms the well-documented truncating mutations, and missense variants represent a clinical dilemma as the pathogenic role is yet to be clearly shown. In this systematic review, we collected these missense variations with a documented deleterious function...
March 8, 2017: European Journal of Cancer Prevention
https://www.readbyqxmd.com/read/28258387/-brca-diagnostics-of-ovarian-cancer-molecular-tumor-testing-since-the-introduction-of-parp-inhibitor-therapy
#14
H Löser, C Heydt, R Büttner, B Markiefka
Approximately 9000 women are diagnosed with ovarian cancer in Germany each year. The most common subtype is high-grade serous ovarian cancer. A relevant proportion of these tumors are associated with mutations in the breast and ovarian cancer susceptibility genes (BRCA1 and BRCA2) representing highly penetrant tumor suppressor genes with autosomal inheritance and play a crucial role in DNA repair mechanisms. These patients have predominantly germline mutations and less frequently have somatic BRCA mutations...
March 3, 2017: Der Pathologe
https://www.readbyqxmd.com/read/28250726/parp-inhibitors-review-of-mechanisms-of-action-and-brca1-2-mutation-targeting
#15
REVIEW
Karolina N Dziadkowiec, Emilia Gąsiorowska, Ewa Nowak-Markwitz, Anna Jankowska
Poly(ADP-ribose) polymerases have shown true promise in early clinical studies due to reported activity in BRCA-associated cancers. PARP inhibitors may represent a potentially important new class of chemotherapeutic agents directed at targeting cancers with defective DNA-damage repair. In order to widen the prospective patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required. In addition, a more sophisticated understanding of the toxicity profile is required if PARP inhibitors are to be employed in the curative, rather than the palliative, setting...
December 2016: Przeglad Menopauzalny, Menopause Review
https://www.readbyqxmd.com/read/28250698/pharmaceutical-approval-update
#16
Mary Choy
Insulin degludec/liraglutide (Xultophy 100/3.6) for type-2 diabetes; rucaparib (Rubraca) for the treatment of deleterious BRCA mutation-associated ovarian cancer; and nusinersen (Spinraza) for the treatment of spinal muscular atrophy.
March 2017: P & T: a Peer-reviewed Journal for Formulary Management
https://www.readbyqxmd.com/read/28247266/rucaparib-first-global-approval
#17
Yahiya Y Syed
Rucaparib (Rubraca™) is an oral, small molecule, poly (ADP-ribose) polymerase inhibitor being developed by Clovis Oncology, Inc. (Boulder, CO, USA) for the treatment of solid tumours. It has been approved in the USA as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies. A marketing authorization application for rucaparib for the same indication has been submitted to the European Medicines Agency...
March 1, 2017: Drugs
https://www.readbyqxmd.com/read/28246467/familial-pancreatic-cancer-concept-management-and-issues
#18
REVIEW
Hiroyuki Matsubayashi, Kyoichi Takaori, Chigusa Morizane, Hiroyuki Maguchi, Masamichi Mizuma, Hideaki Takahashi, Keita Wada, Hiroko Hosoi, Shinichi Yachida, Masami Suzuki, Risa Usui, Toru Furukawa, Junji Furuse, Takamitsu Sato, Makoto Ueno, Yoshimi Kiyozumi, Susumu Hijioka, Nobumasa Mizuno, Takeshi Terashima, Masaki Mizumoto, Yuzo Kodama, Masako Torishima, Takahisa Kawaguchi, Reiko Ashida, Masayuki Kitano, Keiji Hanada, Masayuki Furukawa, Ken Kawabe, Yoshiyuki Majima, Toru Shimosegawa
Familial pancreatic cancer (FPC) is broadly defined as two first-degree-relatives with pancreatic cancer (PC) and accounts for 4%-10% of PC. Several genetic syndromes, including Peutz-Jeghers syndrome, hereditary pancreatitis, hereditary breast-ovarian cancer syndrome (HBOC), Lynch syndrome, and familial adenomatous polyposis (FAP), also have increased risks of PC, but the narrowest definition of FPC excludes these known syndromes. When compared with other familial tumors, proven genetic alterations are limited to a small proportion (< 20%) and the familial aggregation is usually modest...
February 14, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28242752/phase-i-dose-escalation-2-part-trial-of-poly-adp-ribose-polymerase-inhibitor-talazoparib-in-patients-with-advanced-germline-brca1-2-mutations-and-selected-sporadic-cancers
#19
Johann de Bono, Ramesh K Ramanathan, Lida Mina, Rashmi Chugh, John Glaspy, Saeed Rafii, Stan Kaye, Jasgit Sachdev, John Heymach, David C Smith, Joshua W Henshaw, Ashleigh Herriott, Miranda Patterson, Nicola J Curtin, Lauren Averett Byers, Zev A Wainberg
Talazoparib inhibits poly(ADP-ribose) polymerase (PARP) catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this 2-part, phase I, first-in-human trial. Antitumor activity, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%)...
February 27, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28235830/telomere-length-is-predictive-of-breast-cancer-risk-in-brca2-mutation-carriers
#20
Birna Thorvaldsdottir, Margret Aradottir, Olafur A Stefansson, Sigridur K Bodvarsdottir, Jorunn E Eyfjörd
BACKGROUND: Germline BRCA2 mutations increase risk of breast cancer and other malignancies. BRCA2 has been shown to play a role in telomere protection and maintenance. Telomere length (TL) has been studied as a modifying factor for various diseases, including breast cancer. Previous research on TL in BRCA mutation carriers has produced contradicting results. METHODS: We measured blood TL, using a high-throughput monochrome multiplex qPCR method, in a well-defined Icelandic cohort of female BRCA2 mutation carriers (n=169), sporadic breast cancer patients (n=561) and healthy controls (n=537)...
February 24, 2017: Cancer Epidemiology, Biomarkers & Prevention
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