scholarly journals Impact of Helicobacter pylori Infection and Its Major Virulence Factor CagA on DNA Damage Repair

2020 ◽  
Vol 8 (12) ◽  
pp. 2007
Author(s):  
Eleftherios Kontizas ◽  
Spyros Tastsoglou ◽  
Timokratis Karamitros ◽  
Yiannis Karayiannis ◽  
Panagoula Kollia ◽  
...  
Keyword(s):  
Dna Damage ◽  
Helicobacter Pylori ◽  
Virulence Factor ◽  
Excision Repair ◽  
Dna Damage Repair ◽  
Helicobacter Pylori Infection ◽  
Dna Glycosylase ◽  
Damage Repair ◽  
Increased Risk ◽  
H Pylori

Helicobacter pylori infection induces a plethora of DNA damages. Gastric epithelial cells, in order to maintain genomic integrity, require an integrous DNA damage repair (DDR) machinery, which, however, is reported to be modulated by the infection. CagA is a major H. pylori virulence factor, associated with increased risk for gastric carcinogenesis. Its pathogenic activity is partly regulated by phosphorylation on EPIYA motifs. Our aim was to identify effects of H. pylori infection and CagA on DDR, investigating the transcriptome of AGS cells, infected with wild-type, ΔCagA and EPIYA-phosphorylation-defective strains. Upon RNA-Seq-based transcriptomic analysis, we observed that a notable number of DDR genes were found deregulated during the infection, potentially resulting to base excision repair and mismatch repair compromise and an intricate deregulation of nucleotide excision repair, homologous recombination and non-homologous end-joining. Transcriptome observations were further investigated on the protein expression level, utilizing infections of AGS and GES-1 cells. We observed that CagA contributed to the downregulation of Nth Like DNA Glycosylase 1 (NTHL1), MutY DNA Glycosylase (MUTYH), Flap Structure-Specific Endonuclease 1 (FEN1), RAD51 Recombinase, DNA Polymerase Delta Catalytic Subunit (POLD1), and DNA Ligase 1 (LIG1) and, contrary to transcriptome results, Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APE1) upregulation. Our study accentuates the role of CagA as a significant contributor of H. pylori infection-mediated DDR modulation, potentially disrupting the balance between DNA damage and repair, thus favoring genomic instability and carcinogenesis.

Interaction of 22 risk SNPs with Helicobacter pylori infection and risk of gastric cardia adenocarcinoma

2019 ◽  
Vol 15 (31) ◽  
pp. 3579-3585 ◽  
Author(s):  
Fan-Kai Xiao ◽  
Jian Xue Yang ◽  
Xin Min Li ◽  
Xue Ke Zhao ◽  
Peng Yuan Zheng ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Helicobacter Pylori Infection ◽  
Gastric Cardia ◽  
Gastric Cardia Adenocarcinoma ◽  
Susceptibility Loci ◽  
Single Nucleotide ◽  
Increased Risk ◽  
Risk Snps ◽  
H Pylori ◽  
The Relationship

Aim: To determine the prevalence of Helicobacter pylori infection and correlation between H. pylori infection and single nucleotide polymorphism (SNPs) identified in gastric cardia adenocarcinoma (GCA) patients. Methods: A case control study was performed. 22 risks of GCA-related SNPs were identified by genotyping assay and the relationship between susceptibility loci for GCA and H. pylori infection was further analyzed. Results: Helicobacter pylori infection was associated with GCA significantly (odds ratio: 1.40; 95% CI: 1.29–1.53 p < 0.01). Five GCA risk SNPs had their genotypes significantly different between H. pylori positive patients and H. pylori negative patients. Conclusion: The interaction between SNPs susceptibility loci and H. pylori infection is associated with an increased risk of GCA.

scholarly journals Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making

2017 ◽  
pp. 1-16 ◽  
Author(s):  
Wassim Abida ◽  
Joshua Armenia ◽  
Anuradha Gopalan ◽  
Ryan Brennan ◽  
Michael Walsh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Clinical Decision Making ◽  
Dna Damage Repair ◽  
Genomic Profiling ◽  
Castration Resistant Prostate Cancer ◽  
Disease States ◽  
Castration Resistant ◽  
Damage Repair ◽  
Increased Risk

Purpose A long natural history and a predominant osseous pattern of metastatic spread are impediments to the adoption of precision medicine in patients with prostate cancer. To establish the feasibility of clinical genomic profiling in this disease, we performed targeted deep sequencing of tumor and normal DNA from patients with locoregional, metastatic noncastrate, and metastatic castration-resistant prostate cancer. Patients and Methods Patients consented to genomic analysis of their tumor and germline DNA. A hybridization capture-based clinical assay was used to identify single-nucleotide variations, small insertions and deletions, copy number alterations, and structural rearrangements in more than 300 cancer-related genes in tumors and matched normal blood. Results We successfully sequenced 504 tumors from 451 patients with prostate cancer. Potentially actionable alterations were identified in DNA damage repair, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase pathways. Twenty-seven percent of patients harbored a germline or a somatic alteration in a DNA damage repair gene that may predict for response to poly (ADP-ribose) polymerase inhibition. Profiling of matched tumors from individual patients revealed that somatic TP53 and BRCA2 alterations arose early in tumors from patients who eventually developed metastatic disease. In contrast, comparative analysis across disease states revealed that APC alterations were enriched in metastatic tumors, whereas ATM alterations were specifically enriched in castration-resistant prostate cancer. Conclusion Through genomic profiling of prostate tumors that represent the disease clinical spectrum, we identified a high frequency of potentially actionable alterations and possible drivers of disease initiation, metastasis, and castration resistance. Our findings support the routine use of tumor and germline DNA profiling for patients with advanced prostate cancer for the purpose of guiding enrollment in targeted clinical trials and counseling families at increased risk of malignancy.

scholarly journals Helicobacter pylori Genes Involved in Avoidance of Mutations Induced by 8-Oxoguanine

2006 ◽  
Vol 188 (21) ◽  
pp. 7464-7469 ◽  
Author(s):  
Aurélie Mathieu ◽  
Eyleen J. O'Rourke ◽  
J. Pablo Radicella
Keyword(s):  
Helicobacter Pylori ◽  
Excision Repair ◽  
Spontaneous Mutation ◽  
Chromosomal Rearrangements ◽  
Dna Glycosylase ◽  
Endonuclease Activity ◽  
Abasic Site ◽  
E Coli ◽  
Cell Extracts ◽  
H Pylori

ABSTRACT Chromosomal rearrangements and base substitutions contribute to the large intraspecies genetic diversity of Helicobacter pylori. Here we explored the base excision repair pathway for the highly mutagenic 8-oxo-7,8-dihydroguanine (8-oxoG), a ubiquitous form of oxidized guanine. In most organisms, 8-oxoG is removed by a specific DNA glycosylase (Fpg in bacteria or OGG1 in eukaryotes). In the case where replication of the lesion yields an A/8-oxoG base pair, a second DNA glycosylase (MutY) can excise the adenine and thus avoid the fixation of the mutation in the next round of replication. In a genetic screen for H. pylori genes complementing the hypermutator phenotype of an Escherichia coli fpg mutY strain, open reading frame HP0142, a putative MutY coding gene, was isolated. Besides its capacity to complement E. coli mutY strains, HP0142 expression resulted in a strong adenine DNA glycosylase activity in E. coli mutY extracts. Consistently, the purified protein also exhibited such an activity. Inactivation of HP0142 in H. pylori resulted in an increase in spontaneous mutation frequencies. An Mg-dependent AP (abasic site) endonuclease activity, potentially allowing the processing of the abasic site resulting from H. pylori MutY activity, was detected in H. pylori cell extracts. Disruption of HP1526, a putative xth homolog, confirmed that this gene is responsible for the AP endonuclease activity. The lack of evidence for an Fpg/OGG1 functional homolog is also discussed.

scholarly journals Targeted DNA Damage Repair CRISPR/Cas9 Knockout Screen Identifies Novel Classification of Poly-ADP Ribose Polymerase Inhibitors Based on Key Base Excision Repair Proteins

2020 ◽  
Author(s):  
Gregory A. Breuer ◽  
Jonathan Bezney ◽  
Nathan R. Fons ◽  
Ranjini K. Sundaram ◽  
Wanjuan Feng ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Parp Inhibition ◽  
Brca1 And Brca2 ◽  
Damage Repair ◽  
Base Excision

ABSTRACTDNA repair deficiencies have become an increasingly promising target for novel therapeutics within the realm of clinical oncology. Recently, a number of inhibitors of Poly(ADP-ribose) Polymerases (PARPs) have received approval for the treatment of ovarian cancers with and without deleterious mutations in the homologous recombination proteins BRCA1 and BRCA2. Unfortunately, as over a hundred clinical trials are actively underway testing the utility of PARP inhibition across dozens of unique cancers, the mechanism of action for such inhibitors remains unclear. While many believe PARP trapping to be the most important determinant driving the cytotoxicity found in such inhibitors, clinically effective inhibitors exist which possess both strong and weak PARP-trapping qualities. Such results indicate that characterization of inhibitors as strong and weak trappers does not properly capture the intra-class characteristics of such small molecule inhibitors. Using a novel, targeted DNA damage repair and response (DDR) CRISPR/Cas9 screening library, we describe a new classification scheme for PARP inhibitors that revolves around sensitivity to key modulators of the base excision repair (BER) pathway, unrelated to trapping ability or catalytic inhibition of PARP. These findings demonstrate that inhibition of PARylation and induction of PARP trapping are not the only factors responsible for the clinical response of DDR-deficient cancers to PARP inhibition, and provide insight into the optimal choice of PARP inhibitor to be used in the setting of additional DNA repair deficiencies.

scholarly journals Rare coding variants in five DNA damage repair genes associate with timing of natural menopause

2021 ◽  
Author(s):  
Lucas D Ward ◽  
Margaret M Parker ◽  
Aimee M Deaton ◽  
Ho-Chou Tu ◽  
Alexander O Flynn-Carroll ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Disease Risk ◽  
Polycystic Ovary ◽  
Dna Damage Repair ◽  
Cancer Genes ◽  
Natural Menopause ◽  
Cell Counts ◽  
Damage Repair ◽  
Increased Risk

The age of menopause is associated with fertility and disease risk, and its genetic control is of great interest. We used whole-exome sequences from 119,992 women in the UK Biobank to test for associations between rare damaging variants and age at natural menopause. Rare damaging variants in three genes significantly associated with menopause: CHEK2 (p = 6.2 × 10-51) and DCLRE1A (p = 1.2 × 10-12) with later menopause and TOP3A (p = 8.8 × 10-8) with earlier menopause. Two additional genes were suggestive: RAD54L (p = 2.3 × 10-6) with later menopause and HROB (p = 2.7 × 10-6) with earlier menopause. In a follow-up analysis of repeated questionnaires in women who were initially pre-menopausal, CHEK2, TOP3A, and RAD54L genotype associated with subsequent menopause. Consistent with previous GWAS, all five genes are involved in the DNA-damage repair pathway. Phenome-wide scans across 363,977 men and women revealed that in addition to known associations with cancers and blood cell counts, rare variants in CHEK2 also associated with increased risk of uterine fibroids, polycystic ovary syndrome, and prostate hypertrophy; these associations are not shared with higher-penetrance breast cancer genes. Causal mediation analysis suggests that approximately 8% of the breast cancer risk conferred by CHEK2 pathogenic variants after menopause is mediated through delayed menopause.

scholarly journals Relationship of interleukin-1B gene promoter region polymorphism with Helicobacter pylori infection and gastritis

2015 ◽  
Vol 9 (10) ◽  
pp. 1108-1116 ◽  
Author(s):  
Ivy Bastos Ramis ◽  
Júlia Silveira Vianna ◽  
Priscila Cristina Bartolomeu Halicki ◽  
Caroline Lara ◽  
Thássia Fernanda Tadiotto ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Promoter Region ◽  
Gene Promoter ◽  
Helicobacter Pylori Infection ◽  
Caga Gene ◽  
Gastric Diseases ◽  
Ulcer Disease ◽  
Increased Risk ◽  
H Pylori ◽  
Relationship Of

Introduction: Helicobacter pylori infection is associated with gastritis, peptic ulcer disease and gastric carcinoma. The severity of damage is determined by the interplay between environmental/behavioral factors, bacterial pathogenicity genes and host genetic polymorphisms that can influence the secretion levels of inflammatory cytokines. Accordingly, this study aimed to identify polymorphisms in the IL-1B and IL-1RN genes and their associations with H. pylori infection, cagA gene of H. pylori, and gastroduodenal diseases. Methodology: Gastric biopsy samples from 151 patients infected with H. pylori and 76 uninfected individuals were analyzed. H. pylori infection was diagnosed by histology and PCR. Polymorphisms at positions -511, -31 and +3954 of the IL-1B gene were detected by PCR-RFLP, and an analysis of the VNTR polymorphism of the IL-1RN gene was performed by PCR. Results: It was observed that the presence of the T/T genotype at position -511 and the C/C genotype at position -31 were associated with H. pylori infection and with an increased risk of gastritis in H. pylori-positive patients. Additionally, strains from patients H. pylori-positive carrying the cagA gene was significantly related with the T/T genotype at position -511 of IL-1B.  No association of polymorphisms at position +3954 of IL-1B and in the IL-1RN with H. pylori infection and with risk of severe gastric diseases was found. Conclusions: We demonstrated that polymorphisms in the promoter region of the IL-1B gene (at positions -511 and -31) are associated with an enhanced risk of H. pylori infection as well as gastritis in H. pylori-positive patients.

Role of nucleotide excision repair proteins in oxidative DNA damage repair: an updating

2011 ◽  
Vol 76 (1) ◽  
pp. 4-15 ◽  
Author(s):  
B. Pascucci ◽  
M. D’Errico ◽  
E. Parlanti ◽  
S. Giovannini ◽  
E. Dogliotti
Keyword(s):  
Dna Damage ◽  
Nucleotide Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Dna Damage Repair ◽  
Damage Repair ◽  
Nucleotide Excision

Alterations of DNA damage repair genes in Chinese colorectal cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16121-e16121
Author(s):  
Wenliang Li ◽  
Zhu Zhu ◽  
Ning Xu ◽  
Wei Huang ◽  
Junping Shi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Excision Repair ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Dna Damage Repair ◽  
Molecular Characteristics ◽  
Damage Repair

e16121 Background: Colorectal cancer (CRC) is the second most common cancer in women and third in men. DNA damage repair (DDR) deficiency has emerged as a predictive biomarker for chemotherapy, PARP and immune checkpoint inhibitors. However, comprehensive molecular characteristics of DDR variants in Chinese CRC patients is lacking. Methods: Formalin fixed, paraffin embedded (FFPE) tumor tissues and matched blood samples were collected for targeted next-generation sequencing (NGS) assay. The testing was carried out in a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Alterations of six functional gene sets involved in DDR pathways: homologous recombination (HR), mismatch repair (MMR), base excision repair (BER), nonhomologous end-joining (NHEJ), checkpoint factors (CPF) and Fanconi anemia (FA) were analyzed. The association of DDR gene mutations with TMB/MSI was assessed. Results: In total, 319 CRC patients were recruited, 127 female and 192 male with a median age of 59 (range 23-92). Over one third (36%,115/319) patients had at least one mutation in DDR genes. Mutation rates varied in different DDR pathway: HR (20.7%), CPF (15.1%), FA (11.3%), MMR (10.3%), BER (8.8%), and NHEJ (5.3%). The most frequently mutated DDR genes were ARID1A (13.4%), ATM (10.2%), BRCA2 (6.8%), MLH1 (5.6%), MSH6 (5.6%), POLE (5.0%). Germline mutations in MLH1 (2.5%), BRCA2 (1.2%), MSH2 (0.9%), MSH6 (0.9%), FANCA (0.9%), ATM (0.6%), BRCA1 (0.3%), and CHEK2 (0.3%) were detected in 24 patients. DDR variations were enriched in the right-side CRC compared to the left side CRC (50% vs. 32.8%, p= 0.024). Early stage (I-II) harbored more DDR variations. 20.1% of patients had high TMB (≥10 muts/Mb) with a median of 51 muts/Mb (10-326.7 mus/Mb). Patients with DDR mutations had a significantly higher TMB than patients with wild type DDR (8.5 vs. 4.6 muts/Mb, p< 0.001). All CRC tumors with high MSI harbored DDR mutations. Importantly, the mutations in “HM” (HR/MMR), but not BER/CPF/NHEJ/FA mutations, were significantly correlated with high MSI ( p< 0.001). Conclusions: DDR gene alterations occurred in 36% of Chinese CRC patients and were enriched in right sided tumors. DDR pathway alterations are relatively frequent in CRC and consideration for biomarker-enriched clinical trials with PARP, immune checkpoint inhibitors, and novel combinations are warranted.

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