Genetic Susceptibility to Oral Cancer due to Combined Effects of GSTT1, GSTM1 and CYP1A1 Gene Variants in Tobacco Addicted Patients of Pashtun Ethnicity of Khyber Pakhtunkhwa Province of Pakistan

Abstract

Associations of GSTT1, GSTM1 and CYP1A1 gene variants with risk of developing oral cancer were evaluated in this study. A case-control study was conducted in Pashtun population of Khyber Pakhtunkhwa province of Pakistan in which 200 hospital based oral cancer cases and 151 population based healthy controls exposed to similar environmental conditions were included. Sociodemographic data were obtained and blood samples were collected with informed consent for analysis. GSTM1 and GSTT1 were analysed through conventional PCR method while specific RT-PCR method was used to detect CYP1A1 polymorphisms. Results were analyzed for conditional logistic regression model by SPSS version 20. The study shows that patients with either GSTM1 or GSTT1 null genotypes have significantly higher risk of oral cancer (adjusted odds (OR): (3.019 (1.861-4.898) and 3.011(1.865-4.862), respectively), which further increased when either one or both null genes were present in combination (adjusted odds (OR): (3.627 (1.981-6.642 and 9.261 (4.495-19.079), respectively). CYP1A1 rs4646903 gene variants individually showed weak association OR: 1.121 (0.717-1.752); however, in the presence of GSTM1 and/or GSTT1 null genotypes further increasing the association (adjusted odds (ORs): 4.576 (2.038-10.273), 5.593 (2.530-12.362) and 16.10 (3.854-67.260 for GSTM/GSTT null and CYP1A1 wild type, GSTM/GSTT either null and CYP1A1 variant alleles, and all 3 gene polymorphisms combinations, respectively). Our findings suggest that presence of GSTM1 and/or GSTT1 null genotypes along with variant alleles of CYP1A1 may be the risk alleles for oral cancer susceptibility in Pashtun population.

Preliminary Study of the GSTM1 Null Polymorphism and History of Tobacco Smoking among Oral Cancer Patients in Northeastern Thailand

“…GSTM1 polymorphism is one of the most studied loci vis-à-vis the risk of oral cancer. Homozygous deletion results in functional loss of GSTM1 enzyme (Gronau et al, 2003), which has been implicated in the genesis of several types of cancer (Schnakenberg et al, 2000;Tiwawech et al, 2005;Liu et al, 2014;Zakiullah et al, 2015). However, in this well designed case-control study with age -and sex-matched controls, the GSTM1 null genotype or the genotype distribution was not significantly associated with an increased risk of OSCC among northeastern Thais.…”

“…The absence of the homozygous allele of the GSTM1 gene (GSTM1 null genotype) results in a complete loss of enzyme activity for binding with genotoxic substrates; including the epoxides derived from aflatoxin and PAHs, resulting in a decreased capacity to detoxify carcinogens (Hayes andPulford, 1995, Sreelekha et al, 2001). It is believed that individuals with the GSTM1 null genotype lack the functional ability to detoxify the ultimate form of carcinogens and are, therefore, susceptible to cancer in various organs (including the lung, bladder, oral and nasopharynx) (Schnakenberg et al, 2000;Shield PG., 2002;Tiwawech et al, 2005;Liu et al, 2014;Zakiullah et al, 2015). Results of many other studies dealing with the association between GSTM1 polymorphism in some of these cancers have, however, proven contradictory (Tanimoto et al, 1999;Hahn et al, 2002;Natphopsuk et al, 2015).…”

The Fagerström and AUDIT Tests as Probable Screening Tools in Oral Cancer and Their Correlation with CYP1A1, GSTM1, GSTP1, and GSTT1 Gene Expression

“…We did not observe differences in GSTM1 , GSTP1 , or GSTT1 gene expression in the cancer group, but as Phase II enzymes are responsible for detoxification of carcinogens, once cancer is present, it possibly means that the role of these enzymes is not proceeded to neutralize the toxic substances. The greater correlation found between CYP1A1 expression and tumor size, and regional metastases reinforce the hypothesis that the more bioactivation and presence of carcinogens, the poorest outcome can be found [ 47 ].…”

Association of Glutathione-S-Transferases M1 and T1 Deletional Variants with Development of Oral Squamous Cell Carcinoma: A Study in the South-East of Iran

“…"M" denotes DNA marker. Tanwar et al, 2015) and 17.6% to 47.5% for null-GSTT1 (Zakiullah et al, 2015;Peters et al, 2006). We found no Iranian studies reporting these genotypes in OSCC patients.…”

“…The expression of GST isoforms has been suggested as a diagnostic biomarker and a disease-monitoring factor in cancers of squamous cells (Li et al, 2014). Zakiullah et al, (2015) indicated that non-functional GSTT1 and GSTM1 genes led to increasing oral cancer by three-times. Furthermore, they showed that simultaneous deletion of one allele from each gene of these variables significantly increased the chance for cancer incidence.…”