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[PMID]: 29427417
[Au] Autor:Hu L; Huang W; Bei L; Broglie L; Eklund EA
[Ad] Address:Northwestern University, Chicago, IL 60611.
[Ti] Title: Haploinsufficiency Rescues Emergency Granulopoiesis in Mice.
[So] Source:J Immunol;200(6):2129-2139, 2018 Mar 15.
[Is] ISSN:1550-6606
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Emergency (stress) granulopoiesis is an episodic process for the production of granulocytes in response to infectious challenge. We previously determined that Fanconi C, a component of the Fanconi DNA-repair pathway, is necessary for successful emergency granulopoiesis. Fanconi anemia results from mutation of any gene in this pathway and is characterized by bone marrow failure (BMF) in childhood and clonal progression in adolescence. Although murine Fanconi anemia models exhibit relatively normal steady-state hematopoiesis, mice are unable to mount an emergency granulopoiesis response. Instead, these mice develop BMF and die during repeated unsuccessful emergency granulopoiesis attempts. In mice, BMF is associated with extensive apoptosis of hematopoietic stem and progenitor cells through an undefined mechanism. In this study, we find that haploinsufficiency completely rescues emergency granulopoiesis in mice and protects them from BMF during repeated emergency granulopoiesis episodes. Instead, such recurrent challenges accelerated clonal progression in mice. In mice, BMF during multiple emergency granulopoiesis attempts was associated with increased ataxia telangiectasia and Rad3-related protein (Atr) and p53 activation with each attempt. In contrast, we found progressive attenuation of expression and activity of Atr, and consequent p53 activation and apoptosis, in the bone marrow of mice during this process. Therefore, activation of Atr-with consequent Fanconi-mediated DNA repair or p53-dependent apoptosis-is an essential component of emergency granulopoiesis and it protects the bone marrow from genotoxic stress during this process.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:In-Data-Review
[do] DOI:10.4049/jimmunol.1700931

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[PMID]: 29307578
[Au] Autor:Li X; Wilson AF; Du W; Pang Q
[Ad] Address:Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
[Ti] Title:Cell-Cycle-Specific Function of p53 in Fanconi Anemia Hematopoietic Stem and Progenitor Cell Proliferation.
[So] Source:Stem Cell Reports;10(2):339-346, 2018 Feb 13.
[Is] ISSN:2213-6711
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Overactive p53 has been proposed as an important pathophysiological factor for bone marrow failure syndromes, including Fanconi anemia (FA). Here, we report a p53-dependent effect on hematopoietic stem and progenitor cell (HSPC) proliferation in mice deficient for the FA gene Fanca. Deletion of p53 in Fanca mice leads to replicative exhaustion of the hematopoietic stem cell (HSC) in transplant recipients. Using Fanca HSCs expressing the separation-of-function mutant p53 transgene, which selectively impairs the p53 function in apoptosis but keeps its cell-cycle checkpoint activities intact, we show that the p53 cell-cycle function is specifically required for the regulation of Fanca HSC proliferation. Our results demonstrate that p53 plays a compensatory role in preventing FA HSCs from replicative exhaustion and suggest a cautious approach to manipulating p53 signaling as a therapeutic utility in FA.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:In-Data-Review

  3 / 7764 MEDLINE  
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[PMID]: 29514982
[Au] Autor:Jin H; Roy U; Lee G; Schärer OD; Cho Y
[Ad] Address:Pohang University of Science and Technology, Korea, Republic of.
[Ti] Title:Structural Mechanism of DNA Interstrand Cross-link Unhooking by Bacterial FAN1 Nuclease.
[So] Source:J Biol Chem;, 2018 Mar 07.
[Is] ISSN:1083-351X
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:DNA interstrand cross-links (ICLs) block the progress of the replication and transcription machineries and can weaken chromosomal stability, resulting in various diseases. FANCD2/FANCI-associated nuclease (FAN1) is a conserved structure-specific nuclease that unhooks DNA ICLs independently of the Fanconi anemia pathway. Recent structural studies have proposed two different mechanistic features for ICL unhooking by human FAN1: a specific basic pocket that recognizes the terminal phosphate of a 1-nt 5' flap or FAN1 dimerization. Herein, we show that despite lacking these features, Pseudomonas aeruginosa FAN1 (PaFAN1) cleaves substrates at ~3-nt intervals and resolves ICLs. Crystal structures of PaFAN1 bound to various DNA substrates revealed that its conserved basic R/K patch comprising Arg-228 and Lys-260 recognizes phosphate groups near the 5' terminus of a DNA substrate with a 1-nt flap or a nick. Substitution of Lys-260 did not affect PaFAN1's initial endonuclease activity, but significantly decreased its subsequent exonuclease activity and ICL unhooking. The R/K patch also interacted with phosphates at a 3-nt gap, and this interaction could drive movement of the scissile phosphates into the PaFAN1 active site. In human FAN1, the ICL-resolving activity was not affected by individual disruption of the R/K patch or basic pocket. However, simultaneous substitution of both FAN1 regions significantly reduced its ICL-resolving activity, suggesting that these two basic regions play a complementary role in ICL repair. On the basis of these findings, we propose a conserved role for two basic regions in FAN1 to guide ICL unhooking and maintain genomic stability.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[St] Status:Publisher

  4 / 7764 MEDLINE  
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[PMID]: 29514101
[Au] Autor:Ferris E; Abegglen LM; Schiffman JD; Gregg C
[Ad] Address:Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132-3401, USA.
[Ti] Title:Accelerated Evolution in Distinctive Species Reveals Candidate Elements for Clinically Relevant Traits, Including Mutation and Cancer Resistance.
[So] Source:Cell Rep;22(10):2742-2755, 2018 Mar 06.
[Is] ISSN:2211-1247
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The identity of most functional elements in the mammalian genome and the phenotypes they impact are unclear. Here, we perform a genome-wide comparative analysis of patterns of accelerated evolution in species with highly distinctive traits to discover candidate functional elements for clinically important phenotypes. We identify accelerated regions (ARs) in the elephant, hibernating bat, orca, dolphin, naked mole rat, and thirteen-lined ground squirrel lineages in mammalian conserved regions, uncovering ∼33,000 elements that bind hundreds of different regulatory proteins in humans and mice. ARs in the elephant, the largest land mammal, are uniquely enriched near elephant DNA damage response genes. The genomic hotspot for elephant ARs is the E3 ligase subunit of the Fanconi anemia complex, a master regulator of DNA repair. Additionally, ARs in the six species are associated with specific human clinical phenotypes that have apparent concordance with overt traits in each species.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180307
[Lr] Last revision date:180307
[St] Status:In-Data-Review

  5 / 7764 MEDLINE  
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[PMID]: 29452344
[Au] Autor:Birkbak NJ; Li Y; Pathania S; Greene-Colozzi A; Dreze M; Bowman-Colin C; Sztupinszki Z; Krzystanek M; Diossy M; Tung N; Ryan PD; Garber JE; Silver DP; Iglehart JD; Wang ZC; Szuts D; Szallasi Z; Richardson AL
[Ad] Address:Department of Bio and Health Informatics, Technical University of Denmark, Lyngby, Denmark.
[Ti] Title:Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple negative breast and serous ovarian cancers.
[So] Source:Ann Oncol;, 2018 Feb 14.
[Is] ISSN:1569-8041
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Background: Platinum based therapy is an effective treatment for a subset of triple negative breast cancer and ovarian cancer patients. In order to increase response rate and decrease unnecessary use, robust biomarkers that predict response to therapy are needed. Patients and methods: We performed an integrated genomic approach combining differential analysis of gene expression and DNA copy number in sensitive compared to resistant triple negative breast cancers in two independent neoadjuvant cisplatin treated cohorts. Functional relevance of significant hits was investigated in vitro by overexpression, knockdown and targeted inhibitor treatment. Results: We identified two genes, the Bloom helicase (BLM) and Fanconi anemia complementation group I (FANCI), that have both increased DNA copy number and gene expression in the platinum sensitive cases. Increased level of expression of these two genes was also associated with platinum but not with taxane response in ovarian cancer. As a functional validation, we found that overexpression of BLM promotes DNA damage and induces sensitivity to cisplatin, but has no effect on paclitaxel sensitivity. Conclusions: A biomarker based on the expression levels of the BLM and FANCI genes is a potential predictor of platinum sensitivity in triple negative breast cancer and ovarian cancer. Short description: Through integrated analysis of gene expression and copy number data from two independent clinical trials in triple negative breast cancer, we identify two genes, BLM and FANCI, involved in double-strand DNA repair where increased expression is related to sensitivity to platinum induced DNA damage. Further functional validation reveals that overexpression of BLM alone promotes DNA damage.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[St] Status:Publisher
[do] DOI:10.1093/annonc/mdy049

  6 / 7764 MEDLINE  
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[PMID]: 29206995
[Au] Autor:Wyatt AW; Annala M; Aggarwal R; Beja K; Feng F; Youngren J; Foye A; Lloyd P; Nykter M; Beer TM; Alumkal JJ; Thomas GV; Reiter RE; Rettig MB; Evans CP; Gao AC; Chi KN; Small EJ; Gleave ME
[Ad] Address:Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada; Institute of Biosciences and Medical Technology, University of Tampere, Tampere, Finland; Department of Medicine and Department of Radiation Oncology, UCSF Helen Diller Family Comprehensive
[Ti] Title:Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer.
[So] Source:J Natl Cancer Inst;109(12), 2017 Dec 01.
[Is] ISSN:1460-2105
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Background: Real-time knowledge of the somatic genome can influence management of patients with metastatic castration-resistant prostate cancer (mCRPC). While routine metastatic tissue biopsy is challenging in mCRPC, plasma circulating tumor DNA (ctDNA) has emerged as a minimally invasive tool to sample the tumor genome. However, no systematic comparisons of matched "liquid" and "solid" biopsies have been performed that would enable ctDNA profiling to replace the need for direct tissue sampling. Methods: We performed targeted sequencing across 72 clinically relevant genes in 45 plasma cell-free DNA (cfDNA) samples collected at time of metastatic tissue biopsy. We compared ctDNA alterations with exome sequencing data generated from matched tissue and quantified the concordance of mutations and copy number alterations using the Fisher exact test and Pearson correlations. Results: Seventy-five point six percent of cfDNA samples had a ctDNA proportion greater than 2% of total cfDNA. In these patients, all somatic mutations identified in matched metastatic tissue biopsies were concurrently present in ctDNA. Furthermore, the hierarchy of variant allele fractions for shared mutations was remarkably similar between ctDNA and tissue. Copy number profiles between matched liquid and solid biopsy were highly correlated, and individual copy number calls in clinically actionable genes were 88.9% concordant. Detected alterations included AR amplifications in 22 (64.7%) samples, SPOP mutations in three (8.8%) samples, and inactivating alterations in tumor suppressors TP53 , PTEN , RB1 , APC , CDKN1B , BRCA2 , and PIK3R1 . In several patients, ctDNA sequencing revealed robust changes not present in paired solid biopsy, including clinically relevant alterations in the AR, WNT, and PI3K pathways. Conclusions: Our study shows that, in the majority of patients, a ctDNA assay is sufficient to identify all driver DNA alterations present in matched metastatic tissue and supports development of DNA biomarkers to guide mCRPC patient management based on ctDNA alone.
[Mh] MeSH terms primary: Circulating Tumor DNA/blood
Prostatic Neoplasms, Castration-Resistant/genetics
Prostatic Neoplasms, Castration-Resistant/pathology
[Mh] MeSH terms secundary: Adenomatous Polyposis Coli Protein/genetics
BRCA2 Protein/genetics
Biomarkers, Tumor/blood
Biomarkers, Tumor/genetics
Cyclin-Dependent Kinase Inhibitor p27/genetics
DNA Copy Number Variations
Humans
Liquid Biopsy
Male
Mutation
Neoplasm Metastasis
Nuclear Proteins/genetics
PTEN Phosphohydrolase/genetics
Phosphatidylinositol 3-Kinases/genetics
Receptors, Androgen/genetics
Repressor Proteins/genetics
Retinoblastoma Binding Proteins/genetics
Tumor Suppressor Protein p53/genetics
Ubiquitin-Protein Ligases/genetics
Wnt Signaling Pathway/genetics
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (APC protein, human); 0 (Adenomatous Polyposis Coli Protein); 0 (BRCA2 Protein); 0 (BRCA2 protein, human); 0 (Biomarkers, Tumor); 0 (CDKN1B protein, human); 0 (Circulating Tumor DNA); 0 (Nuclear Proteins); 0 (RB1 protein, human); 0 (Receptors, Androgen); 0 (Repressor Proteins); 0 (Retinoblastoma Binding Proteins); 0 (SPOP protein, human); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 2.7.1.- (PIK3R1 protein, human); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 3.1.3.67 (PTEN Phosphohydrolase); EC 3.1.3.67 (PTEN protein, human)
[Em] Entry month:1712
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[Js] Journal subset:IM
[Da] Date of entry for processing:171206
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djx118

  7 / 7764 MEDLINE  
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[PMID]: 29511342
[Au] Autor:García-Calderón CB; Bejarano-García JA; Tinoco-Gago I; Castro MJ; Moreno-Gordillo P; Piruat JI; Caballero-Velázquez T; Pérez-Simón JA; Rosado IV
[Ad] Address:Instituto de Biomedicina de Sevilla (IBiS)/CSIC/Universidad de Sevilla/Campus Hospital Universitario Vírgen del Rocío, 41013, Seville, Spain.
[Ti] Title:Genotoxicity of tetrahydrofolic acid to hematopoietic stem and progenitor cells.
[So] Source:Cell Death Differ;, 2018 Mar 06.
[Is] ISSN:1476-5403
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Metabolically reactive formaldehyde is a genotoxin and a carcinogen. Mice lacking the main formaldehyde-detoxifying gene Adh5 combined with the loss of the Fanconi anemia (FA) DNA repair pathway rapidly succumbed to bone marrow failure (BMF) primarily due to the extensive ablation of the hematopoietic stem cell (HSC) pool. However, the mechanism by which formaldehyde mediates these toxic effects is still unknown. We uncover a detrimental role of tetrahydrofolic acid (THF) in cells lacking Adh5 or the FA repair pathway. We show that Adh5- or FA-deficient cells are hypersensitive to formaldehyde and to THF, presenting DNA damage and genome instability. THF cytotoxicity involved imbalance of the nucleotide pool by deregulation of the thymidylate synthase (TYMS) enzyme, which stalled replication forks. In mice, THF exposure had widespread effects on hematopoiesis, affecting the frequency and the viability of myeloid- and lymphoid-committed precursor cells. Moreover, the hematopoietic stem and progenitor cells (HSPC) showed genomic instability, reduced colony-forming capacity and increased frequency of cycling and apoptotic HSCs upon THF exposure. Overall, our data reveal that the physiological pool of THF and formaldehyde challenge the stability of the genome of HSPCs that might lead to blood disorders.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180307
[Lr] Last revision date:180307
[St] Status:Publisher
[do] DOI:10.1038/s41418-018-0089-4

  8 / 7764 MEDLINE  
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[PMID]: 29325268
[Au] Autor:Li MJ; Li HR; Cheng X; Bi R; Tu XY; Liu F; Chen LH
[Ad] Address:Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
[Ti] Title:[Clinical significance of targeting drug-based molecular biomarkers expression in ovarian clear cell carcinoma].
[So] Source:Zhonghua Fu Chan Ke Za Zhi;52(12):835-843, 2017 Dec 25.
[Is] ISSN:0529-567X
[Cp] Country of publication:China
[La] Language:chi
[Ab] Abstract:To assess the expression level of targeting drug-based molecular biomarkers in ovarian clear cell carcinoma (OCCC) tissues and its clinical significance. A total of 63 OCCC patients included 40 primary OCCC and 23 recurrent OCCC for secondary cytoreductive surgery (SCS), who had received primary surgeries at Fudan University Shanghai Cancer Center between January, 2008 and December, 2015 were enrolled, and immunohistochemistry SP method was used to test human epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER2), aurora kinase A (AURKA), breast cancer susceptibility gene 1 (BRCA1), BRCA2 and programmed death-ligand 1 (PD-L1)protein expression in paraffin-embedded tissues. The positive rates of EGFR, HER2, AURKA,BRCA1, BRCA2 and PD-L1 in primary and recurrent tumor tissues were respectively 20% (8/40) vs 30% (7/23) , 22% (9/40) vs 35% (8/23) , 38% (15/40) vs 35% (8/23) , 42% (17/40) vs 39% (9/23) , 20% (8/40) vs 22% (5/23) , 25% (10/40) vs 17% (4/23) , and there were no significant differences between primary and recurrent OCCC (all 0.05). χ(2)-test or Fisher exact analysis revealed that HER2 expression in recurrent tumor tissues had a relationship with chemoresistance ( 0.05), while the expression of other biomarkers showed no significant relationship with chemoresistance (all 0.05). Further, Kaplan-Meier survival analysis showed that patients with HER2 and AURKA-positive expression had a significantly shorter progression-free survival time in primary OCCC (4 months vs 10 months, log-rank test, 0.05 for HER2; and 4 months vs 10 months, 0.05 for AURKA); and a shorter overall survival time after SCS in recurrent OCCC (10 months vs 44 months, 0.05 for HER2; and 13 months vs 43 months, 0.05 for AURKA). However, multivariate Cox proportional hazards regression analysis indicated that none of these 6 biomarkers was independent risk factor of progression-free survival time of primary OCCC or overall survival time after SCS for recurrent OCCC ( 0.05). HER2 and AURKA could serve as prognostic factors in ovarian clear cell carcinoma.
[Mh] MeSH terms primary: Adenocarcinoma, Clear Cell/drug therapy
Adenocarcinoma, Clear Cell/metabolism
Biomarkers, Tumor/metabolism
Neoplasms, Glandular and Epithelial/drug therapy
Neoplasms, Glandular and Epithelial/metabolism
Ovarian Neoplasms/drug therapy
Ovarian Neoplasms/metabolism
Precision Medicine
[Mh] MeSH terms secundary: Adenocarcinoma, Clear Cell/diagnosis
Adenocarcinoma, Clear Cell/mortality
BRCA2 Protein
China
Disease-Free Survival
Female
Humans
Immunohistochemistry
Kaplan-Meier Estimate
Molecular Targeted Therapy
Neoplasm Recurrence, Local
Neoplasms, Glandular and Epithelial/diagnosis
Neoplasms, Glandular and Epithelial/mortality
Ovarian Neoplasms/diagnosis
Ovarian Neoplasms/mortality
Receptor, Epidermal Growth Factor
Receptor, ErbB-2
Survival Analysis
Treatment Outcome
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (BRCA2 Protein); 0 (BRCA2 protein, human); 0 (Biomarkers, Tumor); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.10.1 (Receptor, ErbB-2)
[Em] Entry month:1803
[Cu] Class update date: 180306
[Lr] Last revision date:180306
[Js] Journal subset:IM
[Da] Date of entry for processing:180112
[St] Status:MEDLINE
[do] DOI:10.3760/cma.j.issn.0529-567x.2017.12.008

  9 / 7764 MEDLINE  
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[PMID]: 29491055
[Au] Autor:Glaas MF; Wiek C; Wolter LM; Roellecke K; Balz V; Okpanyi V; Wagenmann M; Hoffmann TK; Grässlin R; Plettenberg C; Schipper J; Hanenberg H; Scheckenbach K
[Ad] Address:Department of Otorhinolaryngology & Head/Neck Surgery, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany.
[Ti] Title:Mutational and Functional Analysis of as a Candidate Gene for Sporadic Head and Neck Squamous Cell Carcinomas.
[So] Source:Anticancer Res;38(3):1317-1325, 2018 03.
[Is] ISSN:1791-7530
[Cp] Country of publication:Greece
[La] Language:eng
[Ab] Abstract:BACKGROUND/AIM: Head and neck squamous cell carcinomas (HNSCCs) form a heterogeneous tumor entity located throughout the oral cavity, pharynx and larynx that is caused predominantly by chemically or virally induced carcinogenesis. Heterozygous germline mutations in cancer susceptibility genes might also lead to increased incidence of HNSCCs. As DNA stability is typically impaired in HNSCC cells and genes of the Fanconi anemia/BRCA DNA repair pathway can be mutated or down-regulated in HNSCCs, we investigated here whether germline mutations occur in the X-chromosomal FANCB as candidate gene. MATERIALS AND METHODS: Germline DNA of 85 consecutive HNSCC patients was sequenced. Missense alterations in FANCB were functionally tested in reference cells. RESULTS AND CONCLUSION: Four single nucleotide polymorphisms were identified, three of which were located in untranslated regions of FANCB (rs2188383, rs2375729, rs2905223) and predicted to be associated with normal function. One missense alteration, c.1004G>A resulting in p.G335E (rs41309679), in exon 4 was detected in five men in homozygous and in five women in heterozygous state. Four in silico prediction programs uniformally predicted p.G335E to be associated with loss-of-function of the protein. To clarify these predictions, we expressed the FANCB p.G335E protein in primary human FANCB deficient fibroblasts. Cell cycle analysis of these fibroblasts established that the FANCB p.G335E was functionally indistinguishable from the wildtype FANCB protein. Thus, functional studies in genetically defined cells showed that the p.G335E germline alteration in FANCB is not associated with impaired function.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180305
[Lr] Last revision date:180305
[St] Status:In-Process

  10 / 7764 MEDLINE  
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[PMID]: 29480828
[Au] Autor:Huang YW
[Ti] Title:Association of BRCA1/2 mutations with ovarian cancer prognosis: An updated meta-analysis.
[So] Source:Medicine (Baltimore);97(2):e9380, 2018 Jan.
[Is] ISSN:1536-5964
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:OBJECTIVE: A meta-analysis was performed to determine if BRCA1/2 mutations are associated with improved overall survival (OS) and progression-free survival (PFS) in patients with ovarian cancer. RESEARCH DESIGN AND METHODS: Studies of patients with primary or recurrent ovarian cancer that examined the relationship between BRCA1/2 mutation status and outcomes were included. MAIN OUTCOME MEASURES: The primary outcomes were OS and PFS of patients with and without BRCA1 and BRCA2 mutations. The secondary outcome was treatment response: complete response, partial response, and overall response. RESULTS: Overall analysis revealed BRCA1/2 mutations were associated with improved OS [hazard ratio (HR) = 0.75; 95% confidence interval (CI): 0.64, 0.88; P < .001] and PFS (HR = 0.80; 95% CI: 0.64, 0.99; P = .039). BRCA1 mutations were significantly associated with improved OS (HR = 0.75) but not PFS, and BRCA2 mutations alone were not associated with either improved OS or PFS. The presence of BCRA1/2 mutations was associated with a better overall response rate, higher complete response rate, and lower partial response rate; however, BRCA1 or BRCA2 alone was not associated with overall response rate. CONCLUSIONS: BRCA1 mutations appear to be associated with improved OS in patients with ovarian cancer. However, the effect of BRCA1 mutations on PFS and BRCA2 mutations alone on OS and PFS is less clear.
[Mh] MeSH terms primary: BRCA1 Protein/genetics
BRCA2 Protein/genetics
Mutation
Ovarian Neoplasms/genetics
[Mh] MeSH terms secundary: Female
Humans
Prognosis
[Pt] Publication type:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Name of substance:0 (BRCA1 Protein); 0 (BRCA1 protein, human); 0 (BRCA2 Protein); 0 (BRCA2 protein, human)
[Em] Entry month:1803
[Cu] Class update date: 180302
[Lr] Last revision date:180302
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:180227
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009380


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