Polymorphic DNA repair and metabolic genes: a multigenic study on gastric cancer.
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.
Palli
Domenico
D
Molecular and Nutritional Epidemiology Unit, ISPO (Cancer Prevention and Research Institute), Via Cosimo il Vecchio 2, 50139 Florence, Italy.
Polidoro
Silvia
S
D'Errico
Mariarosaria
M
Saieva
Calogero
C
Guarrera
Simonetta
S
Calcagnile
Angelo S
AS
Sera
Francesco
F
Allione
Alessandra
A
Gemma
Simonetta
S
Zanna
Ines
I
Filomena
Alessandro
A
Testai
Emanuela
E
Caini
Saverio
S
Moretti
Renato
R
Gomez-Miguel
Maria-Jesus
MJ
Nesi
Gabriella
G
Luzzi
Ida
I
Ottini
Laura
L
Masala
Giovanna
G
Matullo
Giuseppe
G
Dogliotti
Eugenia
E
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*
D045643:DNA Repair Enzymes