scholarly journals The XRCC4 rs1805377 polymorphism is not associated with the risk of cancer: An updated meta-analysis

2020 ◽  
Vol 48 (6) ◽  
pp. 030006052092636
Author(s):  
Xin-yuan Zhang ◽  
Xiao-han Wei ◽  
Bao-jie Wang ◽  
Jun Yao
Keyword(s):  
Genetic Model ◽  
Cancer Susceptibility ◽  
Meta Analysis ◽  
Double Strand Breaks ◽  
Inclusion Criteria ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Cancer Susceptibility Genes ◽  
Cancer Occurrence ◽  
Risk Of Cancer

Objectives A growing number of studies have reported that genes involved in the repair of DNA double-strand breaks might be cancer-susceptibility genes. The x-ray cross-complementing group 4 gene ( XRCC4) encodes a protein that functions in the repair of DNA double-strand breaks, and this meta-analysis aimed to investigate the relationship between the XRCC4 rs1805377 polymorphism and cancer occurrence. Methods We retrieved case–control studies that met the inclusion criteria from PubMed, Web of Science, Embase, and China National Knowledge Infrastructure databases. Associations between rs1805377 and cancer risk were evaluated by odds ratios (ORs) using a random effects model and 95% confidence intervals (CIs) as well as sensitivity and subgroup analyses. Results After inclusion criteria were met, the meta-analysis involved 24 studies that included 9,633 cancer patients and 10,544 healthy controls. No significant association was found between rs1805377 and the risk of cancer (pooled OR = 1.107; 95% CI = 0.955–1.284) in the dominant genetic model. Similarly, no significant association was observed in the subgroup analysis. Conclusions Through this meta-analysis, we found no association between the rs1805377 polymorphism and cancer occurrence. This may provide useful information for relevant future studies into the etiology of cancer.

scholarly journals An updated meta-analysis of XRCC4 rs1805377 polymorphism and the risk of cancer based on 23 case-control studies

2019 ◽  
Author(s):  
Xin-yuan Zhang ◽  
Xiao-han Wei ◽  
Bao-jie Wang ◽  
Jun Yao
Keyword(s):  
Subgroup Analysis ◽  
Cancer Susceptibility ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Pooled Analysis ◽  
Dna Double Strand Breaks ◽  
Case Control Studies ◽  
Cancer Susceptibility Genes ◽  
Cancer Occurrence ◽  
Risk Of Cancer

Abstract Background The growing studies reports that the genes participating in repairing of DNA double-strand breaks may be cancer-susceptibility genes. Rs1805377 (A>G) is a functional single nucleotide polymorphism (SNP) in the x-ray cross-complementing group 4 (XRCC4) gene that may be involved in the etiology of cancer. However, no conclusive results can be determined from individually published studies. Thus, we performed a meta-analysis to examine the association between XRCC4 rs1805377 polymorphism and cancer risk.Methods The potential literatures were searched using three online electronic databases (PubMed, Embase, and Web of Science). The available studies were included according to the inclusion criteria. The pooled analysis were performed to explore the association between XRCC4 rs1805377 locus and the risk of cancer. Additionally, we also performed subgroup analysis and sensitivity analysis.Results Twenty-three studies were included in our meta-analysis. It contained 9,433 cancer patients and 10,337 healthy controls. The pooled results showed that there was no association between rs1805377 and the risk of cancer. Under the dominant model, the final pooled odds ratios (ORs) was 1.115 (95% confidence intervals: 0.956-1.301; P = 0.165) in a random effects model without the statistical significance. The subgroup analysis by ethnicity and source of controls also didn’t find that rs1805377 polymorphism was related to cancer occurrence. In the subgroup by type of cancers, the significant association was only found in gastric antrum adenocarcinoma.Conclusions our meta-analysis suggested that there was no association between rs1805377 polymorphism and cancer occurrence. It may provide useful information for the relevant studies on the etiology of cancer in future.

scholarly journals The BRCA2-MEILB2-BRME1 complex governs meiotic recombination and impairs the mitotic BRCA2-RAD51 function in cancer cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jingjing Zhang ◽  
Manickam Gurusaran ◽  
Yasuhiro Fujiwara ◽  
Kexin Zhang ◽  
Meriem Echbarthi ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Breast Cancer Susceptibility ◽  
Double Strand Breaks ◽  
Breast Cancer Susceptibility Gene ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
C Terminus ◽  
Self Association ◽  
Cancer Susceptibility Gene

AbstractBreast cancer susceptibility gene II (BRCA2) is central in homologous recombination (HR). In meiosis, BRCA2 binds to MEILB2 to localize to DNA double-strand breaks (DSBs). Here, we identify BRCA2 and MEILB2-associating protein 1 (BRME1), which functions as a stabilizer of MEILB2 by binding to an α-helical N-terminus of MEILB2 and preventing MEILB2 self-association. BRCA2 binds to the C-terminus of MEILB2, resulting in the formation of the BRCA2-MEILB2-BRME1 ternary complex. In Brme1 knockout (Brme1−/−) mice, the BRCA2-MEILB2 complex is destabilized, leading to defects in DSB repair, homolog synapsis, and crossover formation. Persistent DSBs in Brme1−/− reactivate the somatic-like DNA-damage response, which repairs DSBs but cannot complement the crossover formation defects. Further, MEILB2-BRME1 is activated in many human cancers, and somatically expressed MEILB2-BRME1 impairs mitotic HR. Thus, the meiotic BRCA2 complex is central in meiotic HR, and its misregulation is implicated in cancer development.

scholarly journals Validation of a Semiautomated Natural Language Processing–Based Procedure for Meta-Analysis of Cancer Susceptibility Gene Penetrance

2019 ◽  
pp. 1-9 ◽  
Author(s):  
Zhengyi Deng ◽  
Kanhua Yin ◽  
Yujia Bao ◽  
Victor Diego Armengol ◽  
Cathy Wang ◽  
...  
Keyword(s):  
Natural Language Processing ◽  
Natural Language ◽  
Language Processing ◽  
Cancer Susceptibility ◽  
Meta Analysis ◽  
Susceptibility Gene ◽  
Cancer Susceptibility Genes ◽  
Traditional Procedure ◽  
Meta Analyses ◽  
Risk Of Cancer

PURPOSE Quantifying the risk of cancer associated with pathogenic mutations in germline cancer susceptibility genes—that is, penetrance—enables the personalization of preventive management strategies. Conducting a meta-analysis is the best way to obtain robust risk estimates. We have previously developed a natural language processing (NLP) –based abstract classifier which classifies abstracts as relevant to penetrance, prevalence of mutations, both, or neither. In this work, we evaluate the performance of this NLP-based procedure. MATERIALS AND METHODS We compared the semiautomated NLP-based procedure, which involves automated abstract classification and text mining, followed by human review of identified studies, with the traditional procedure that requires human review of all studies. Ten high-quality gene–cancer penetrance meta-analyses spanning 16 gene–cancer associations were used as the gold standard by which to evaluate the performance of our procedure. For each meta-analysis, we evaluated the number of abstracts that required human review (workload) and the ability to identify the studies that were included by the authors in their quantitative analysis (coverage). RESULTS Compared with the traditional procedure, the semiautomated NLP-based procedure led to a lower workload across all 10 meta-analyses, with an overall 84% reduction (2,774 abstracts v 16,941 abstracts) in the amount of human review required. Overall coverage was 93%—we are able to identify 132 of 142 studies—before reviewing references of identified studies. Reasons for the 10 missed studies included blank and poorly written abstracts. After reviewing references, nine of the previously missed studies were identified and coverage improved to 99% (141 of 142 studies). CONCLUSION We demonstrated that an NLP-based procedure can significantly reduce the review workload without compromising the ability to identify relevant studies. NLP algorithms have promising potential for reducing human efforts in the literature review process.

scholarly journals Fanconi Anemia FANCG Protein in Mitigating Radiation- and Enzyme-Induced DNA Double-Strand Breaks by Homologous Recombination in Vertebrate Cells

2003 ◽  
Vol 23 (15) ◽  
pp. 5421-5430 ◽  
Author(s):  
Kazuhiko Yamamoto ◽  
Masamichi Ishiai ◽  
Nobuko Matsushita ◽  
Hiroshi Arakawa ◽  
Jane E. Lamerdin ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Chromosome Breakage ◽  
Breast Cancer Susceptibility ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Brca1 And Brca2 ◽  
Strand Breaks

ABSTRACT The rare hereditary disorder Fanconi anemia (FA) is characterized by progressive bone marrow failure, congenital skeletal abnormality, elevated susceptibility to cancer, and cellular hypersensitivity to DNA cross-linking chemicals and sometimes other DNA-damaging agents. Molecular cloning identified six causative genes (FANCA, -C, -D2, -E, -F, and -G) encoding a multiprotein complex whose precise biochemical function remains elusive. Recent studies implicate this complex in DNA damage responses that are linked to the breast cancer susceptibility proteins BRCA1 and BRCA2. Mutations in BRCA2, which participates in homologous recombination (HR), are the underlying cause in some FA patients. To elucidate the roles of FA genes in HR, we disrupted the FANCG/XRCC9 locus in the chicken B-cell line DT40. FANCG-deficient DT40 cells resemble mammalian fancg mutants in that they are sensitive to killing by cisplatin and mitomycin C (MMC) and exhibit increased MMC and radiation-induced chromosome breakage. We find that the repair of I-SceI-induced chromosomal double-strand breaks (DSBs) by HR is decreased ∼9-fold in fancg cells compared with the parental and FANCG-complemented cells. In addition, the efficiency of gene targeting is mildly decreased in FANCG-deficient cells, but depends on the specific locus. We conclude that FANCG is required for efficient HR-mediated repair of at least some types of DSBs.

Ability to repair DNA double-strand breaks related to cancer susceptibility and radiosensitivity

2007 ◽  
Vol 25 (9) ◽  
pp. 433-438 ◽  
Author(s):  
Koh-ichi Sakata ◽  
Masanori Someya ◽  
Yoshihisa Matsumoto ◽  
Masato Hareyama
Keyword(s):  
Cancer Susceptibility ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks

Functions of BRCA1 and BRCA2 in the biological response to DNA damage

2001 ◽  
Vol 114 (20) ◽  
pp. 3591-3598 ◽  
Author(s):  
Ashok R. Venkitaraman
Keyword(s):  
Dna Damage ◽  
Mammalian Cells ◽  
Cancer Susceptibility ◽  
Biological Response ◽  
Breast Cancer Susceptibility ◽  
Dna Double Strand Breaks ◽  
Brca1 And Brca2 ◽  
Strand Breaks ◽  
Cancer Susceptibility Genes ◽  
And Function

Inheritance of one defective copy of either of the two breast-cancer-susceptibility genes, BRCA1 and BRCA2, predisposes individuals to breast, ovarian and other cancers. Both genes encode very large protein products; these bear little resemblance to one another or to other known proteins, and their precise biological functions remain uncertain. Recent studies reveal that the BRCA proteins are required for maintenance of chromosomal stability in mammalian cells and function in the biological response to DNA damage. The new work suggests that, although the phenotypic consequences of their disruption are similar, BRCA1 and BRCA2 play distinct roles in the mechanisms that lead to the repair of DNA double-strand breaks.

Exploring the roles of PALB2 at the crossroads of DNA repair and cancer

2014 ◽  
Vol 460 (3) ◽  
pp. 331-342 ◽  
Author(s):  
Joris Pauty ◽  
Amélie Rodrigue ◽  
Anthony Couturier ◽  
Rémi Buisson ◽  
Jean-Yves Masson
Keyword(s):  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Developmental Abnormalities ◽  
Strand Breaks ◽  
Primary Focus ◽  
Biallelic Mutations ◽  
A Current

PALB2 [partner and localizer of BRCA2 (breast cancer early-onset 1)] has emerged as a key player in the maintenance of genome integrity. Biallelic mutations in PALB2 cause FA (Fanconi's anaemia) subtype FA-N, a devastating inherited disorder marked by developmental abnormalities, bone marrow failure and childhood cancer susceptibility, whereas monoallelic mutations predispose to breast, ovarian and pancreatic cancer. The tumour suppressor role of PALB2 has been intimately linked to its ability to promote HR (homologous recombination)-mediated repair of DNA double-strand breaks. Because PALB2 lies at the crossroads between FA, HR and cancer susceptibility, understanding its function has become the primary focus of several studies. The present review discusses a current synthesis of the contribution of PALB2 to these pathways. We also provide a molecular description of FA- or cancer-associated PALB2 mutations.

scholarly journals Mechanistic Insights From Single-Molecule Studies of Repair of Double Strand Breaks

2021 ◽  
Vol 9 ◽  
Author(s):  
Muwen Kong ◽  
Eric C. Greene
Keyword(s):  
Single Molecule ◽  
Genome Stability ◽  
Double Strand Breaks ◽  
Complex Nature ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Ensemble Averaging ◽  
Strand Breaks ◽  
Single Molecule Studies ◽  
Risk Of Cancer

DNA double strand breaks (DSBs) are among some of the most deleterious forms of DNA damage. Left unrepaired, they are detrimental to genome stability, leading to high risk of cancer. Two major mechanisms are responsible for the repair of DSBs, homologous recombination (HR) and nonhomologous end joining (NHEJ). The complex nature of both pathways, involving a myriad of protein factors functioning in a highly coordinated manner at distinct stages of repair, lend themselves to detailed mechanistic studies using the latest single-molecule techniques. In avoiding ensemble averaging effects inherent to traditional biochemical or genetic methods, single-molecule studies have painted an increasingly detailed picture for every step of the DSB repair processes.

Repair pathway choice for double-strand breaks

2020 ◽  
Vol 64 (5) ◽  
pp. 765-777 ◽  
Author(s):  
Yixi Xu ◽  
Dongyi Xu
Keyword(s):  
Cell Cycle ◽  
Double Strand Breaks ◽  
Homologous Region ◽  
Gene Repair ◽  
Repair Pathway ◽  
Dna Double Strand Breaks ◽  
Environmental Radiation ◽  
Strand Breaks ◽  
Dna End Resection ◽  
End Resection

Abstract Deoxyribonucleic acid (DNA) is at a constant risk of damage from endogenous substances, environmental radiation, and chemical stressors. DNA double-strand breaks (DSBs) pose a significant threat to genomic integrity and cell survival. There are two major pathways for DSB repair: nonhomologous end-joining (NHEJ) and homologous recombination (HR). The extent of DNA end resection, which determines the length of the 3′ single-stranded DNA (ssDNA) overhang, is the primary factor that determines whether repair is carried out via NHEJ or HR. NHEJ, which does not require a 3′ ssDNA tail, occurs throughout the cell cycle. 53BP1 and the cofactors PTIP or RIF1-shieldin protect the broken DNA end, inhibit long-range end resection and thus promote NHEJ. In contrast, HR mainly occurs during the S/G2 phase and requires DNA end processing to create a 3′ tail that can invade a homologous region, ensuring faithful gene repair. BRCA1 and the cofactors CtIP, EXO1, BLM/DNA2, and the MRE11–RAD50–NBS1 (MRN) complex promote DNA end resection and thus HR. DNA resection is influenced by the cell cycle, the chromatin environment, and the complexity of the DNA end break. Herein, we summarize the key factors involved in repair pathway selection for DSBs and discuss recent related publications.

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