Asian Pacifc Journal of Cancer Prevention, Vol 12, 2011 491 Genetic Variations in Carcinogen Metabolizing Genes Associated with Oral Cancer in the Pakistani Population Asian Pacifc J Cancer Prev, 12, 491-495 Introduction Incidence of oral cancer has increased in the last few years in South East Asia (Buch et al., 2002; Devasena et al., 2007), probably due to increased intake of tobacco. Numerous epidemiological studies indicate that xenobiotic metabolizing genes polymorphisms are associated with increased risk of oral cancer. Most carcinogens are metabolized via complex enzymatic mechanism involving both activation by phase I enzymes and detoxifcation by phase II enzymes. The phase I enzymes are responsible for either detoxifcation of xenobiotic or converting them into an intermediate compound that can be recognized by the phase II enzymes. Phase II enzymes make these compounds more electrophilic and easily detoxifed. So far, 4 different sequence polymorphisms have been reported in CYP1A1 gene, frst known as CYP1A1*2 involves a T6235 to C transition in the 3’ noncoding region (Kawajiri et al., 1990; Jun et al., 2010), second known as CYP1A1*3 involve a A4889 to G transition in exon 7 (Hayashi et al., 1991; Jun et al., 2010), third known as Biosciences, COMSATS Institute of Information and Technology, Islamabad, Pakistan *For correspondence : nosheenmasood@ hotmail.com Abstract Background: Xenobiotics are metabolized by either phase I enzymes like CYP1A1 or phase II enzymes like GSTs. Polymorphisms in the encoding genes (CYP1A1, GSTM1, GSTT1 and GSTP1) potentially may thererfore contribute towards risk association for oral cancer. Methodology: These genes were investigated via a case control study consisting of 228 oral cancer patients and 150 cancer free normal individuals as controls. DNA was extracted 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 were analyzed by multiplex PCR. Results: Two novel mutations were found in this study in relation to oral cancer. A substitution mutation of A2842 with C resulting in missense tyrosine to serine formation along with a frameshift mutation due to insertion of thymidine at nucleotide 2842 resulting in 495 nucleotide sequence to alter was found in oral cancer patients. GSTM1 and GSTT1 deletion polymorphism was found in signifcantly higher number of individuals (OR=2.08, CI 1.05-4.2; OR=1.5, CI 0.9-2.4 respectively) compared to controls. 10 patients had deletion of both GSTM1 and GSTT1 genes. GSTP1 gene was also found to have novel substitution mutations of A2848 to T and G2849 to A in exon 7 resulting in leucine to leucine and alanine to threonine formation respectively. Two intronic deletions of cytosine at positions 1074 and 1466 was found in intron 3 and 4 in patients and no control had these exonic or intronic variants in GSTP1 gene. Conclusion: These results suggest that accumulation of genetic changes in CYP1A1, GSTM1, GSTT1 and GSTP1 genes are associated with increased risk of oral cancer. Keywords: Oral cancer - CYP1A1 - GSTM1 - GSTT1 - GSTP1- polymorphisms - Pakistan RESEARCH COMMUNICATION Genetic Variations in Carcinogen Metabolizing Genes Associated with Oral Cancer in Pakistani Population Nosheen Masood * , Mahmood Akhtar Kayani, Fraz Arshad Malik, Ishrat Mahjabeen, Ruqia Mehmood Baig, Rani Faryal CYP1A1*4 involves a T5639 to C transition in intron 7 (Crofts et al., 1993), and fourth known as CYP1A1*5 involves a C4887 to A transition in exon 7 (Cascorbi et al., 1996; Jun et al., 2010). GSTM1 and GSTT1 are frequently reported to show deletions of entire genes in different population (Stacy and Andrew, 2000; Toru et al., 2008). Deletion of GSTM1 and GSTT1 gene are known to lack respective enzyme activity and are said to be null genes (Egan et al., 2004). To date two polymorphic alleles are known for GSTP1, GSTP1*B and GSTP1*C, in addition to the wild-type allele, GSTP*A has been reported in humans (Ali et al., 1997). Both alleles have an A-to-G transition at nucleotide 313 (codon 104), causing an isoleucine-to-valine change. The GSTP1*C allele has, in addition to the substitution at nucleotide 313, a C-to-T transition at nucleotide 341 (codon 113) that changes alanine to valine (Zimniak et al., 1994). The present study was designed to look at the genetic changes of CYP1A1, GSTM1, GSTT1 and GSTP1 genes and their possible association with risk of oral cancer in Pakistani population.