Genetic Variations in Carcinogen Metabolizing Genes Associated with Oral Cancer in Pakistani Population

Background: Xenobiotics are metabolized by either phase I enzymes like CYP1A1 or phase II enzymes likeGSTs. Polymorphisms in the encoding genes (CYP1A1, GSTM1, GSTT1 and GSTP1) potentially may thererforecontribute towards risk association for oral cancer. Methodology: These genes were investigated via a casecontrol study consisting of 228 oral cancer patients and 150 cancer free normal individuals as controls. DNA wasextracted from WBCs for genotyping. Polymerase chain reaction–single stranded conformational polymorphism(SSCP) was used for screening CYP1A1 and GSTP1 genes mutations. Deletion of GSTM1 and GSTT1 genes wereanalyzed by multiplex PCR.
Results: Two novel mutations were found in this study in relation to oral cancer. Asubstitution mutation of A2842 with C resulting in missense tyrosine to serine formation along with a frameshiftmutation due to insertion of thymidine at nucleotide 2842 resulting in 495 nucleotide sequence to alter was foundin oral cancer patients. GSTM1 and GSTT1 deletion polymorphism was found in significantly higher number ofindividuals (OR=2.08, CI 1.05-4.2; OR=1.5, CI 0.9-2.4 respectively) compared to controls. 10 patients had deletionof both GSTM1 and GSTT1 genes. GSTP1 gene was also found to have novel substitution mutations of A2848 toT and G2849 to A in exon 7 resulting in leucine to leucine and alanine to threonine formation respectively. Twointronic deletions of cytosine at positions 1074 and 1466 was found in intron 3 and 4 in patients and no controlhad these exonic or intronic variants in GSTP1 gene.
Conclusion: These results suggest that accumulation ofgenetic changes in CYP1A1, GSTM1, GSTT1 and GSTP1 genes are associated with increased risk of oral cancer.