title: Polymorphic DNA repair and metabolic genes: a multigenic study on gastric cancer.
abstract: Risk factors for gastric cancer (GC) include inter-individual variability in the inflammatory response to Helicobacter pylori infection, in the ability of detoxifying DNA reactive species and repairing DNA damage generated by oxidative stress and dietary carcinogens. To evaluate the association between polymorphic DNA repair genes and GC risk, a case-control study including 314 histologically confirmed GC patients and 548 healthy controls was conducted in a GC high-risk area in Tuscany, Italy. Polymorphic variants of base excision repair (APE1-D148E, XRCC1-R194W, XRCC1-R399Q and OGG1-S326C), nucleotide excision repair (XPC-PAT, XPA-23G>A, ERCC1-19007T>C and XPD-L751Q), recombination (XRCC3-T241M) and alkylation damage reversal (MGMT-L84F) were tested for their potential role in the development of GC by using logistic regression models. The same population was also characterised for GSTT1 and GSTM1 variant alleles to search for possible functional interactions between metabolic and DNA repair genotypes by two-way interactions using multivariate logistic models. No significant association between any single DNA repair genotype and GC risk was detected with a borderline association with the XPC-PAT homozygous genotype [odds ratio (OR) =1.42; 95% confidence interval (CI) 0.94-2.17]. Gene-gene interaction analysis revealed combinations of unfavourable genotypes involving either multiple DNA repair polymorphisms or DNA repair and GST-specific genotypes. The combination of the XPC-PAT and the XPA variant alleles significantly increased GC risk (OR=2.15; 95% CI 1.17-3.93, P=0.0092). A significant interaction was also found between the APE1 wild-type genotype and either the single GSTT1 (OR=4.90; 95% CI 2.38-10.11, P=0.0079) or double GSTM1-GSTT1 null (OR=7.84; 95% CI 3.19-19.22, P=0.0169) genotypes or the XPA-mutant allele (OR=3.56; 95% CI 1.53-8.25, P=0.0012). These findings indicate that a complex interaction between host factors such as oxidative stress, antioxidant capacity and efficiency of multiple DNA repair pathways underlies the inter-individual variability in GC risk.
authors.affiliation: Molecular and Nutritional Epidemiology Unit, ISPO (Cancer Prevention and Research Institute), Via Cosimo il Vecchio 2, 50139 Florence, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Palli
authors.forename: Silvia
authors.initials: S
authors.lastname: Polidoro
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: D'Errico
authors.forename: Calogero
authors.initials: C
authors.lastname: Saieva
authors.forename: Simonetta
authors.initials: S
authors.lastname: Guarrera
authors.forename: Angelo S
authors.initials: AS
authors.lastname: Calcagnile
authors.forename: Francesco
authors.initials: F
authors.lastname: Sera
authors.forename: Alessandra
authors.initials: A
authors.lastname: Allione
authors.forename: Simonetta
authors.initials: S
authors.lastname: Gemma
authors.forename: Ines
authors.initials: I
authors.lastname: Zanna
authors.forename: Alessandro
authors.initials: A
authors.lastname: Filomena
authors.forename: Emanuela
authors.initials: E
authors.lastname: Testai
authors.forename: Saverio
authors.initials: S
authors.lastname: Caini
authors.forename: Renato
authors.initials: R
authors.lastname: Moretti
authors.forename: Maria-Jesus
authors.initials: MJ
authors.lastname: Gomez-Miguel
authors.forename: Gabriella
authors.initials: G
authors.lastname: Nesi
authors.forename: Ida
authors.initials: I
authors.lastname: Luzzi
authors.forename: Laura
authors.initials: L
authors.lastname: Ottini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Masala
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matullo
authors.forename: Eugenia
authors.initials: E
authors.lastname: Dogliotti
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D016022:Case-Control Studies; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008660:Metabolism / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000502:physiology; D013274:Stomach Neoplasms / Q000235:genetics*
chemical_list: D045643:DNA Repair Enzymes