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.

Polymorphic DNA repair and metabolic genes: a multigenic study on gastric cancer

Polidoro S;D'Errico M;Guarrera S;Allione A;Gemma S;Caini S;Nesi G;Matullo G;
2010

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.
25
6
569
575
http://mutage.oxfordjournals.org/content/early/2010/09/03/mutage.geq042.full.pdf+html
DNA repair; polymorphisms; gastric cancer
Palli D; Polidoro S; D'Errico M; Saieva C; Guarrera S; Calcagnile AS; Sera F; Allione A; Gemma S; Zanna I; Filomena A; Testai E; Caini S; Moretti R; Gomez-Miguel MJ; Nesi G; Luzzi I; Ottini L; Masala G; Matullo G; Dogliotti E
File in questo prodotto:
File Dimensione Formato  
2010_Palli.PDF

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 95.56 kB
Formato Adobe PDF
95.56 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/80389
Citazioni
  • ???jsp.display-item.citation.pmc??? 45
  • Scopus 100
  • ???jsp.display-item.citation.isi??? 96
social impact