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Breast cancer. Dna repair. Brca1. Brca2. Ovarian cancer

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https://www.readbyqxmd.com/read/29145865/the-endonuclease-eepd1-mediates-synthetic-lethality-in-rad52-depleted-brca1-mutant-breast-cancer-cells
#1
Robert Hromas, Hyun-Suk Kim, Gurjit Sidhu, Elizabeth Williamson, Aruna Jaiswal, Taylor A Totterdale, Jocelyn Nole, Suk-Hee Lee, Jac A Nickoloff, Kimi Y Kong
BACKGROUND: Proper repair and restart of stressed replication forks requires intact homologous recombination (HR). HR at stressed replication forks can be initiated by the 5' endonuclease EEPD1, which cleaves the stalled replication fork. Inherited or acquired defects in HR, such as mutations in breast cancer susceptibility protein-1 (BRCA1) or BRCA2, predispose to cancer, including breast and ovarian cancers. In order for these HR-deficient tumor cells to proliferate, they become addicted to a bypass replication fork repair pathway mediated by radiation repair protein 52 (RAD52)...
November 16, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29069866/germline-mutations-in-pancreatic-cancer-and-potential-new-therapeutic-options
#2
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/29021619/pan-cancer-analysis-of-bi-allelic-alterations-in-homologous-recombination-dna-repair-genes
#3
Nadeem Riaz, Pedro Blecua, Raymond S Lim, Ronglai Shen, Daniel S Higginson, Nils Weinhold, Larry Norton, Britta Weigelt, Simon N Powell, Jorge S Reis-Filho
BRCA1 and BRCA2 are involved in homologous recombination (HR) DNA repair and are germ-line cancer pre-disposition genes that result in a syndrome of hereditary breast and ovarian cancer (HBOC). Whether germ-line or somatic alterations in these genes or other members of the HR pathway and if mono- or bi-allelic alterations of HR-related genes have a phenotypic impact on other cancers remains to be fully elucidated. Here, we perform a pan-cancer analysis of The Cancer Genome Atlas (TCGA) data set and observe that bi-allelic pathogenic alterations in homologous recombination (HR) DNA repair-related genes are prevalent across many malignancies...
October 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/28959512/hypoxia-activated-alkylating-agents-in-brca1-mutant-ovarian-serous-carcinoma
#4
Michael Conroy, Mitesh J Borad, Alan H Bryce
Breast cancer 1 antigen (BRCA 1) and breast cancer 2 antigen (BRCA2) genes play a significant role in deoxyribonucleic acid (DNA) repair by means of interstrand crosslink repair, and deleterious germline mutations of these are responsible for most hereditary breast and ovarian cancers. Therapeutic strategies which specifically target interstrand crosslink repair can therefore be helpful in patients with harmful mutations. We describe two patients with advanced ovarian cancer and deleterious BRCA1 mutations who were treated with TH-302, a hypoxia-activated alkylating agent...
July 26, 2017: Curēus
https://www.readbyqxmd.com/read/28914618/hereditary-breast-and-ovarian-cancer-syndrome-moving-beyond-brca1-and-brca2
#5
Lien N Hoang, Blake C Gilks
The recent implementation of next generation sequencing and multigene platforms has expanded the spectrum of hereditary breast and ovarian cancer syndrome, beyond the traditional genes BRCA1 and BRCA2. A large number of other moderate penetrance genes have now been uncovered, which also play critical roles in repairing double stranded DNA breaks through the homologous recombination pathway. This review discusses the landmark discoveries of BRCA1 and BRCA2, the homologous repair pathway and new genes discovered in hereditary breast and ovarian cancer syndrome, as well as their clinicopathologic significance and implications for genetic testing...
September 13, 2017: Advances in Anatomic Pathology
https://www.readbyqxmd.com/read/28866612/dna-repair-related-functional-assays-for-the-classification-of-brca1-and-brca2-variants-a-critical-review-and-needs-assessment
#6
REVIEW
Amanda Ewart Toland, Paul R Andreassen
Mutation of BRCA1 and BRCA2 is the most common cause of inherited breast and ovarian cancer. Genetic screens to detect carriers of variants can aid in cancer prevention by identifying individuals with a greater cancer risk and can potentially be used to predict the responsiveness of tumours to therapy. Frequently, classification cannot be performed based on traditional approaches such as segregation analyses, including for many missense variants, which are therefore referred to as variants of uncertain significance (VUS)...
November 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28782087/germline-brca-mutations-in-asian-patients-with-pancreatic-adenocarcinoma-a-prospective-study-evaluating-risk-category-for-genetic-testing
#7
Kyoungmin Lee, Changhoon Yoo, Kyu-Pyo Kim, Kyoung-Jin Park, Heung-Moon Chang, Tae Won Kim, Jae-Lyun Lee, Woochang Lee, Sang Soo Lee, Do Hyun Park, Tae Jun Song, Dong Wan Seo, Sung Koo Lee, Myung-Hwan Kim, Sang Hyun Shin, Dae Wook Hwang, Ki Byung Song, Jae Hoon Lee, Song Cheol Kim, Baek-Yeol Ryoo
Introduction Germline BRCA mutations may have therapeutic implications as surrogate markers of DNA-damage repair status in pancreatic ductal adenocarcinoma (PDAC). We performed a prospective study to evaluate the efficiency of risk criteria based on personal or family history of breast and ovarian cancer for determining germline BRCA mutations in PDAC patients with Asian ethnicity. Methods Between November 2015 and May 2016, we screened consecutive PDAC patients with locally advanced unresectable or metastatic disease who were referred for systemic chemotherapy...
August 7, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28738860/germline-emsy-sequence-alterations-in-hereditary-breast-cancer-and-ovarian-cancer-families
#8
Kirsi M Määttä, Riikka Nurminen, Minna Kankuri-Tammilehto, Anne Kallioniemi, Satu-Leena Laasanen, Johanna Schleutker
BACKGROUND: BRCA1 and BRCA2 mutations explain approximately one-fifth of the inherited susceptibility in high-risk Finnish hereditary breast and ovarian cancer (HBOC) families. EMSY is located in the breast cancer-associated chromosomal region 11q13. The EMSY gene encodes a BRCA2-interacting protein that has been implicated in DNA damage repair and genomic instability. We analysed the role of germline EMSY variation in breast/ovarian cancer predisposition. The present study describes the first EMSY screening in patients with high familial risk for this disease...
July 24, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28591191/reanalysis-of-brca1-2-negative-high-risk-ovarian-cancer-patients-reveals-novel-germline-risk-loci-and-insights-into-missing-heritability
#9
Jaime L Stafford, Gregory Dyson, Nancy K Levin, Sophia Chaudhry, Rita Rosati, Hasini Kalpage, Courtney Wernette, Nancie Petrucelli, Michael S Simon, Michael A Tainsky
While up to 25% of ovarian cancer (OVCA) cases are thought to be due to inherited factors, the majority of genetic risk remains unexplained. To address this gap, we sought to identify previously undescribed OVCA risk variants through the whole exome sequencing (WES) and candidate gene analysis of 48 women with ovarian cancer and selected for high risk of genetic inheritance, yet negative for any known pathogenic variants in either BRCA1 or BRCA2. In silico SNP analysis was employed to identify suspect variants followed by validation using Sanger DNA sequencing...
2017: PloS One
https://www.readbyqxmd.com/read/28500412/-hereditary-breast-and-ovarian-cancer
#10
REVIEW
S F Lax
Hereditary breast and ovarian carcinomas are frequently caused by germline mutations of the BRCA1 and BRCA2 genes (BRCA1/2 syndromes) and are often less associated with other hereditary syndromes such as Li-Fraumeni and Peutz-Jeghers. The BRCA1/2 proteins have a special role in DNA repair. Therefore, loss of function due to mutation causes an accumulation of mutations in other genes and subsequent tumorigenesis at an early age. BRCA1/2 mutations are irregularly distributed over the length of the genes without hot spots, although special mutations are known...
May 12, 2017: Der Pathologe
https://www.readbyqxmd.com/read/28488580/germline-mutations-in-pancreatic-cancer-and-potential-new-therapeutic-options
#11
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...
April 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28299955/niraparib-for-the-treatment-of-ovarian-cancer
#12
REVIEW
Yada Kanjanapan, Stephanie Lheureux, Amit M Oza
Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are being developed in maintenance and recurrence treatment settings in ovarian cancer. They inhibit single-stranded DNA repair, inducing synthetic lethality in cells with underlying homologous recombination deficiency (HRD). Marked responses are seen in ovarian cancers with breast cancer gene 1 (BRCA1) or 2 (BRCA2) mutation, although up to 50% of high-grade serous ovarian cancers (HGSOC) have HRD may also benefit. Areas covered: This review focuses on niraparib (oral PARP I and II inhibitor), its clinical testing in ovarian cancer, including the Myriad MyChoice HRD test as a potential companion diagnostic...
April 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28258387/-brca-diagnostics-of-ovarian-cancer-molecular-tumor-testing-since-the-introduction-of-parp-inhibitor-therapy
#13
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 2017: Der Pathologe
https://www.readbyqxmd.com/read/28184943/analysis-of-chromosomal-radiosensitivity-of-healthy-brca2-mutation-carriers-and-non-carriers-in-brca-families-with-the-g2-micronucleus-assay
#14
Annelot Baert, Julie Depuydt, Tom Van Maerken, Bruce Poppe, Fransiska Malfait, Tim Van Damme, Sylvia De Nobele, Gianpaolo Perletti, Kim De Leeneer, Kathleen B M Claes, Anne Vral
Breast cancer risk drastically increases in individuals with a heterozygous germline BRCA1 or BRCA2 mutation, while it is estimated to equal the population risk for relatives without the familial mutation (non-carriers). The aim of the present study was to use a G2 phase-specific micronucleus assay to investigate whether lymphocytes of healthy BRCA2 mutation carriers are characterized by increased radiosensitivity compared to controls without a family history of breast/ovarian cancer and how this relates to healthy non-carrier relatives...
March 2017: Oncology Reports
https://www.readbyqxmd.com/read/28099152/the-emsy-threonine-207-phospho-site-is-required-for-emsydriven-suppression-of-dna-damage-repair
#15
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...
February 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28058502/a-novel-loss-of-function-heterozygous-brca2-c-8946_8947delag-mutation-found-in-a-chinese-woman-with-family-history-of-breast-cancer
#16
Jing Ma, Jichun Yang, Wenjing Jian, Xianming Wang, Deyong Xiao, Wenjun Xia, Likuan Xiong, Duan Ma
INTRODUCTION: Breast cancer is the most frequent female malignancy worldwide. Among them, some cases have hereditary susceptibility in two leading genes, BRCA1 and BRCA2. Heterozygous germ line mutations in them are related with increased risk of breast, ovarian and other cancer, following autosomal dominant inheritance mode. METHODS AND RESULTS: For purpose of early finding, early diagnosis and early treatment, mutation detecting of BRCA1/2 genes was performed in unselected 300 breast or ovarian patients and unaffected women using next-generation sequencing and then confirmed by Sanger sequencing...
April 2017: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/27739325/a-randomized-phase-ii-study-of-veliparib-with-temozolomide-or-carboplatin-paclitaxel-versus-placebo-with-carboplatin-paclitaxel-in-brca1-2-metastatic-breast-cancer-design-and-rationale
#17
RANDOMIZED CONTROLLED TRIAL
Steven J Isakoff, Shannon Puhalla, Susan M Domchek, Michael Friedlander, Bella Kaufman, Mark Robson, Melinda L Telli, Véronique Diéras, Hyo Sook Han, Judy E Garber, Eric F Johnson, David Maag, Qin Qin, Vincent L Giranda, Stacie P Shepherd
Veliparib is an orally administered poly(ADP-ribose) polymerase inhibitor that is being studied in Phase I-III clinical trials, including Phase III studies in non-small-cell lung cancer, ovarian cancer and breast cancer. Tumor cells with deleterious BRCA1 or BRCA2 mutations are deficient in homologous recombination DNA repair and are intrinsically sensitive to platinum therapy and poly(ADP-ribose) polymerase inhibitors. We describe herein the design and rationale of a Phase II trial investigating whether the addition of veliparib to temozolomide or carboplatin/paclitaxel provides clinical benefit over carboplatin/paclitaxel with placebo in patients with locally recurrent or metastatic breast cancer harboring a deleterious BRCA1 or BRCA2 germline mutation (Trial registration: EudraCT 2011-002913-12, NCT01506609)...
February 2017: Future Oncology
https://www.readbyqxmd.com/read/27710871/trabectedin-as-a-chemotherapy-option-for-patients-with-brca-deficiency
#18
REVIEW
Bradley J Monk, Domenica Lorusso, Antoine Italiano, Stan B Kaye, Miguel Aracil, Adnan Tanović, Maurizio D'Incalci
Trabectedin is a marine-derived product that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and the first anticancer marine drug to be approved by the European Union. It is currently used as a single agent for the treatment of patients with soft tissue sarcoma after failure of anthracyclines and ifosfamide, or for those patients who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin...
November 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/27649245/reappearance-from-obscurity-mammalian-rad52-in-homologous-recombination
#19
REVIEW
Kritika Hanamshet, Olga M Mazina, Alexander V Mazin
Homologous recombination (HR) plays an important role in maintaining genomic integrity. It is responsible for repair of the most harmful DNA lesions, DNA double-strand breaks and inter-strand DNA cross-links. HR function is also essential for proper segregation of homologous chromosomes in meiosis, maintenance of telomeres, and resolving stalled replication forks. Defects in HR often lead to genetic diseases and cancer. Rad52 is one of the key HR proteins, which is evolutionarily conserved from yeast to humans...
September 14, 2016: Genes
https://www.readbyqxmd.com/read/27515922/hereditary-breast-and-ovarian-cancer-new-genes-in-confined-pathways
#20
REVIEW
Finn Cilius Nielsen, Thomas van Overeem Hansen, Claus Storgaard Sørensen
Genetic abnormalities in the DNA repair genes BRCA1 and BRCA2 predispose to hereditary breast and ovarian cancer (HBOC). However, only approximately 25% of cases of HBOC can be ascribed to BRCA1 and BRCA2 mutations. Recently, exome sequencing has uncovered substantial locus heterogeneity among affected families without BRCA1 or BRCA2 mutations. The new pathogenic variants are rare, posing challenges to estimation of risk attribution through patient cohorts. In this Review article, we examine HBOC genes, focusing on their role in genome maintenance, the possibilities for functional testing of putative causal variants and the clinical application of new HBOC genes in cancer risk management and treatment decision-making...
September 2016: Nature Reviews. Cancer
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