ABSTRACT
BACKGROUND: The combined genetic effects of single nucleotide polymorphisms may additively or synergistically contribute to the increased cancer risk. The interactions associated with xenobiotic metabolizing enzymes and transporter protein involved in the biotransformation and transport of xenobiotics could determine the functional outcomes over the independent effects of a single susceptibility gene in the risk of upper aerodigestive tract cancers. METHODS: The hospital-based case-control study evaluated CYP1A1 (*2A and *2C), CYP2E1 (*1B, *5B, and *6), GST (M1, T1, and P1) and ABCB1 3435C>T polymorphisms among 408 histopathologically confirmed cases and 220 controls using polymerase chain reaction based methods in an Indian population. RESULTS: The multivariate logistic regression analyses demonstrated potentially high risk gene-gene interactions with the concurrent deletions of the GSTT1 and GSTM1 genes and GSTP1 variant genotypes (OR 5.81; 95% CI 1.01-40.28), the deletions of GSTT1 and GSTM1 genotypes with variant genotypes of CYP1A1*2A (OR 8.21; 95% CI 1.91-49.48), GSTT1 and GSTM1 deficient genotypes along with CYP2E1*1B variant genotypes (OR 6.73; 95% CI 1.32-22.81), the polymorphic genotypes of ABCB1 and deficient GSTT1 (OR 6.08; 95% CI 2.21-16.76) and an enhanced risk with the combined variant genotypes of CYP1A1*2A, GSTT1 and ABCB1 (OR 11.14; 95% CI 2.70-46.02). CONCLUSION: The findings indicate that the interactions associated with various drug metabolizing enzymes and transporter protein exhibit high risk for UADT cancers than that ascribed to a single susceptible gene. This was particularly established among the polymorphic carriers of CYP1A1*2A, GSTT1 and ABCB1 genes in the population investigated.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Carcinoma, Squamous Cell/genetics , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP2E1/genetics , Epistasis, Genetic , Glutathione Transferase/genetics , Head and Neck Neoplasms/genetics , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Carcinoma, Squamous Cell/enzymology , Carcinoma, Squamous Cell/metabolism , Case-Control Studies , Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP2E1/metabolism , Female , Genetic Predisposition to Disease , Glutathione Transferase/metabolism , Head and Neck Neoplasms/enzymology , Head and Neck Neoplasms/metabolism , Humans , India , Isoenzymes/genetics , Isoenzymes/metabolism , Male , Middle Aged , Polymorphism, Single NucleotideABSTRACT
BACKGROUND AND OBJECTIVE: Upper aerodigestive tract (UADT) cancers are associated with the tobacco use and alcohol consumption. Certain toxins and carcinogens causing UADT cancers are found to be substrates of polymorphic ABCB1 gene encoded P-glycoprotein efflux pump. This study investigates the association between ABCB1 gene polymorphism at exon 26 (3435C>T) and risk to UADT cancers in Tamilians, a population of south India. METHODS: The study included 219 unrelated histopathologically confirmed cases and 210 population-based controls. Genomic DNA was extracted from peripheral leukocytes and genotyped for ABCB1 3435C>T polymorphism by PCR-restriction fragment length polymorphism method. RESULTS: The multivariate logistic regression analyses demonstrated that the homozygous ABCB1 TT genotype was significantly associated with an overall increased risk for developing UADT cancers [odds ratio (OR): 2.53; 95% confidence interval (CI): 1.28-5.02]. Further, the determination of gene-environment interaction by stratified analyses have revealed a significant interaction between the smoking and homozygous TT genotype [(OR: 7.52; CI: 1.50-37.70) and (OR: 16.89; CI: 3.87-73.79) for 11-20 and >20 pack-years, respectively]. The strongest interaction was observed among the regular tobacco chewers (OR: 45.29; CI: 8.94-130.56) homozygous for TT genotype. No suggestion, however, of an interaction between the genotypes and the alcohol consumption on the multiplicative scale was made. CONCLUSION: The ABCB1 gene polymorphism at exon 26 (3435C>T) may be one of the risk factors for susceptibility to UADT cancers. Furthermore, the significant interaction among habitual smokers and tobacco chewers, homozygous for TT genotype modulates the risk to UADT cancers in the Tamilian population of south India.