Cytochrome P450 2A isoenzymes in freshly prepared blood lymphocytes isolated from rats and validation as a biomarker for clinical studies in humans.

1. The present study aimed to identify the expression of carcinogen metabolizing cytochrome P4502A (CYP2A) isoenzymes in freshly prepared rat peripheral blood lymphocytes (PBL) isolated from adult rats and investigate similarities in the regulation of lymphocyte CYP2A-isoenzymes with the tissue enzyme. 2. qRT-PCR studies demonstrated significant constitutive mRNA expression of CYP2A-isoenzymes in PBL isolated from male and female rats which further increases significantly after pretreatment with nicotine or 3-methylcholanthrene (MC) indicating responsiveness of CYP2A-isoenzymes in PBL. This increase in the CYP2A expression was associated with an increase in the protein expression and CYP2A3-dependent coumarin hydroxylase (COH) activity in PBL. 3. Clinical studies further demonstrated significant increase in the expression of CYP2A6 and associated enzyme activity in PBL isolated from lung cancer patients. Our data thus provided evidence for similarities in the regulation of carcinogen metabolizing CYP2A-isoenzymes in PBL with the tissue enzymes. Further, responsiveness of blood CYP2A6 in human blood lymphocytes isolated from lung cancer patients has led us to suggest that associating expression profiles of CYP2A6 and other polycyclic aromatic hydrocarbons (PAH)-responsive CYPs in PBL with the genotyping data could lead to the development of a possible screen to monitor and predict environment-induced diseases and toxicity in humans.

Association of functionally important polymorphism of microsomal epoxide hydrolase gene (EPHX1) with lung cancer susceptibility.

Distribution and gene-environment interaction of EPHX1 polymorphism was evaluated in 175 lung cancer patients and 322 controls from north India. Two novel non-synonymous, Lys117Arg and Leu263Phe, and twelve single nucleotide polymorphisms were identified in the present study. Binary logistic regression analysis showed association of polymorphism Tyr113His with increased risk of lung cancer (OR = 2.2, 95% CI = 1.2-4.0, p < .05). Gene-environment interaction revealed that patients with His113His and smoking habit had significantly greater risk of lung cancer (OR = 4.52, 95% CI = 0.93-43.05, p < .05). Present study provided evidence that EPHX1 polymorphism is associated with lung cancer susceptibility in Indian population.

Polymorphism in glutathione S-transferases: susceptibility and treatment outcome for head and neck cancer.

The study investigates the association of polymorphism in glutathione S-transferases (GSTs) with susceptibility for head and neck squamous cell carcinoma (HNSCC) and its sites as well as treatment response in cases receiving chemotherapy (CT) and combination of CT-radiotherapy (CT-RT). The case-control study included 500 male cases and an equal number of healthy male controls. Odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated for the association between genotypes and cancer risk. An increase in the risk for HNSCC and cancers of oral cavity, larynx or pharynx was observed in cases with null genotypes of GSTM1 or GSTT1. The interaction of alcohol or tobacco with variant genotypes of GSTM1 or GSTT1 also resulted in a significant increase in the risk for HNSCC. Further, HNSCC cases carrying the null genotypes of GSTM1 and GSTT1 or variant genotypes of GSTP1 showed a significant and superior treatment response. The present data thus provides evidence for the association of polymorphisms in GSTs with risk for HNSCC and its treatment response.

Interaction of drug metabolizing cytochrome P450 2D6 poor metabolizers with cytochrome P450 2C9 and 2C19 genotypes modify the susceptibility to head and neck cancer and treatment response.

The present case-control study attempted to investigate the association of poor metabolizer (PM) genotypes of cytochrome P450 2D6 (CYP2D6*4 and CYP2D6*10) with squamous cell carcinoma of head and neck (HNSCC) and treatment response in patients receiving chemotherapy or combination of chemo- and radiotherapy. Cases with the PM genotypes of CYP2D6 displayed a significantly increased risk for HNSCC as compared to wild type genotypes. The risk was found to further increase in cases (up to 4.8) carrying combination of PM genotypes of CYP2D6, CYP2C9 (CYP2C9*2) or CYP2C19 (CYP2C19*2), suggesting that synergism amongst the PM genotypes of drug metabolizing CYPs leads to impairment in the detoxification of the tobacco carcinogens. A small increase in the risk in tobacco (chewers or smokers) or alcohol users in cases with CYP2D6*4 allele while no change or even a small decrease in risk in cases with CYP2D6*10 allele when compared to non-tobacco or alcohol users have suggested that CYP2D6 genotypes alone do not appear to interact significantly with environmental risk factors in modifying the susceptibility to HNSCC. Furthermore, most of the cases carrying PM genotypes of CYP2D6 did not respond to the treatment. Moreover, higher prevalence of non-responders among cases carrying combination of CYP2D6*4 or CYP2D6*4, CYP2C9*2 and CYP2C19*2 have demonstrated that interaction of PM genotypes may not only significantly modify the susceptibility to HNSCC but also the treatment response.

Polymorphism in cytochrome P4501A1 is significantly associated with head and neck cancer risk.

A case control study was undertaken to investigate the association of polymorphisms in cytochrome P4501A1 (CYP1A1) with squamous cell carcinoma of head and neck (HNSCC) in North Indian population. The variant genotypes of CYP1A1*2A and CYP1A1*2C were found to be overrepresented in cases when compared to controls. The HNSCC risk also increased several folds in cases with combination of variant genotypes of CYP1A1*2A or CYP1A1*2C with null genotype of glutathione-S-transferase M1 (GSTM1), a phase II enzyme, particularly in cases who were tobacco users (smokers and tobacco chewers), demonstrating the role of gene-gene and gene-environment interactions in the development of HNSCC.

Polymorphism in cytochrome P450 2A6 and glutathione S-transferase P1 modifies head and neck cancer risk and treatment outcome.

A case control study was carried out to investigate the association of functionally important polymorphism in cytochrome P450 2A6 (CYP2A6) and glutathione S-transferase P1 (GSTP1) genes with head and neck squamous cell carcinoma (HNSCC) and treatment response in cases receiving a combination of chemo-radiotherapy. The study group consisted of 350 males suffering from HNSCC and an equal number of male controls. Multivariate logistic regression analysis revealed statistically significant decrease in risk to HNSCC in cases with variant genotypes (CYP2A6*1B and CYP2A6*4C) of CYP2A6 (OR: 0.78; 95% CI: 0.43-1.22; P=0.04) or GSTP1 (OR: 0.71; 95% CI: 0.51-1.00; P=0.05). The risk associated with these variant genotypes was found to be further decreased in cases carrying a combination of variant genotypes of CYP2A6 and GSTP1 (OR: 0.40; 95% CI: 0.25-0.65; P=0.00). A similar decrease in risk was observed in cases with variant genotypes of CYP2A6 (OR: 0.59; 95% CI: 0.40-0.86; P=0.00) or GSTP1 (OR: 0.62; 95% CI: 0.42-0.91; P=0.01) and who were regular tobacco users (cigarette smokers or tobacco chewers). Interestingly, only 27% of the cases carrying the variant forms of CYP2A6 (*1A/*4C+*1B/*4C+*4C/*4C) responded to the treatment for HNSCC when compared to those with wild-type genotype (69%). However with GSTP1, cases with homozygous mutant genotype (Val/Val) showed a superior treatment response (75%) when compared to cases with wild-type genotype (25%). Further, cases carrying a combination of variant genotype of CYP2A6 and wild-type genotype of GSTP1 exhibited a very poor treatment response demonstrating that polymorphisms in CYP2A6 and GSTP1 not only modified the risk to HNSCC but also played a major role in determining the chemotherapeutic response.

Evidence for increased cytochrome P450 1A1 expression in blood lymphocytes of lung cancer patients.

To develop blood lymphocyte cytochrome P450 1A1 (CYP1A1) expression as a surrogate for monitoring tissue expression for polycyclic aromatic hydrocarbon (PAH) induced toxicity, the present study attempted to characterize CYP1A1 mRNA expression and its associated catalytic activity in freshly prepared blood lymphocytes isolated from healthy controls and patients suffering from tobacco induced lung cancer. Human blood lymphocytes were found to express CYP1A1 mRNA and significant activity of 7-ethoxyresorufin-O-deethylase (EROD). Significant increase in the activity of EROD and CYP1A1 mRNA was observed in blood lymphocytes isolated from patients suffering from lung cancer. Further, controls with variant genotypes of CYP1A1 (Msp1 or Ile/Val polymorphism) exhibited significant increase in the enzyme activity associated with an increase in CYP1A1 mRNA expression when compared to the controls with wild type genotype. Patients with variant genotypes of CYP1A1 also exhibited much greater increase in the blood lymphocyte CYP1A1 mRNA expression and EROD activity when compared to controls or patients with wild type genotype. Our data thus provides evidence of CYP1A1 expression in freshly isolated blood lymphocytes and differences in reactivity in individuals with variant genotypes of CYP1A1, suggesting that blood lymphocyte CYP1A1 expression profile could help in identifying individuals at risk to environment induced lung cancer.

Interaction of cytochrome P4501A1 genotypes with other risk factors and susceptibility to lung cancer.

Lung cancer is the most common cause of death throughout the world with cigarette smoking being established as the major etiological factor in lung cancer. Since not much information is available regarding the polymorphism in drug metabolizing enzymes and lung cancer risk in the Indian population, the present case-control study attempted to investigate the association of polymorphisms in cytochrome P450 1A1 (CYP1A1) and glutathione-S-transferase M1 (GSTM1) with risk to squamous cell carcinoma of lung malignancy. Patients suffering from lung cancer (n=200) and visiting OPD facility of Department of Radiotherapy, King George's Medical University, Lucknow, were included in the study. Equal number (n=200) of age and sex matched healthy individuals were also enrolled in the study. Our data revealed that the variant genotypes of CYP1A1*2A, CYP1A1*2C and CYP1A1*4 were found to be over represented in the lung cancer patients when compared to controls. CYP1A1*2A variant genotypes (combined heterozygous and mutant genotypes) revealed significant association towards the lung cancer risk (OR: 1.93, 95%CI: 1.28-2.89, p=0.002). Likewise, GSTM1 null genotypes were found to be over represented in patients when compared to controls. Haplotype analysis revealed that CYP1A1 haplotype, C-G-C increased the lung cancer risk (OR: 3.90, 95%CI: 1.00-15.04, p=0.025) in the patients. The lung cancer risk was increased several two-to fourfold in the patients carrying the genotype combinations of CYP1A1*2A and GSTM1 suggesting the role of gene-gene interaction in lung cancer. Cigarette smoking or tobacco chewing or alcohol consumption was also found to interact with CYP1A1 genotypes in increasing the risk to lung cancer further demonstrating the role of gene-environment interaction in development of lung cancer.

Association of genetic polymorphisms in glutathione S-transferases and susceptibility to head and neck cancer.

Polymorphism in glutathione S-transferase (GST) genes (GSTM1, GSTT1 and GSTP1) and interaction with environmental factors such as tobacco (smoking or chewing) and alcohol on susceptibility to head and neck squamous cell carcinoma (HNSCC) was studied in a case-control study. The study group consisted of 175 patients suffering from HNSCC and 200 age matched healthy controls. Statistical analysis showed an increase in risk to HNSCC in the patients with null genotype of GSTM1 (OR: 2.02; 95% CI: 1.32-3.10; P=0.001) or GSTT1 (OR: 1.66; 95% CI: 1.02-2.69; P=0.04), though the risk was not found to be significant when adjusted for age, sex, smoking, tobacco chewing or alcohol use by multivariate logistic regression model. Our data further showed that combination of deletion genotypes of GST (GSTM1 and GSTT1) confer an even higher risk of HNSCC. Interestingly, GSTP1 wild type genotype in combination with GSTM1 null or GSTT1 null genotype increased susceptibility for HNSCC (OR: 2.49 and 2.75, respectively). Likewise a much greater risk for HNSCC was observed in the patients carrying a genotype combination of GSTM1 null, GSTT1 null and GSTP1 (Ile/Ile) (OR: 4.47; 95% CI: 1.62-12.31; P=0.002). Our data have further provided evidence that tobacco chewing and alcohol consumption are the important risk factors for HNSCC. The interaction between tobacco chewing and null genotype of GSTM1 or GSTT1 resulted in about 3.5- and 2.2-fold increase in the risk respectively in the patients when compared to those not chewing tobacco. Alcohol use resulted in more than 4-fold increase in the risk in the patients with null genotype of GSTM1 as compared to those who are non-drinkers. Alcohol consumption also increased the risk (approx. 3-fold) in the cases with null genotype of GSTT1, though the association was not found to be significant when compared to non-drinkers. Our data have provided evidence that GST polymorphism modifies the susceptibility to HNSCC and have further demonstrated importance of gene-environment interaction in modulating the risk to HNSCC.

Genetic polymorphisms in cytochrome P4501B1 and susceptibility to head and neck cancer.

Cytochrome P4501B1 (CYP1B1), a polycyclic aromatic hydrocarbon (PAH) metabolizing CYP, is genetically polymorphic in humans and may be involved in the individual susceptibility to chemical-induced cancer. In the present study, genotype and haplotype frequencies of four single nucleotide polymorphisms (SNPs) in CYP1B1 that cause amino acid changes (Arg-Gly at codon 48, Ala-Ser at codon 119, Leu-Val at codon 432 and Asn-Ser at codon 453) were studied in 150 cases suffering from head and neck squamous cell carcinoma (HNSCC) and in an equal number of controls. A significant difference was observed for the distribution of variant genotypes of Arg48Gly (CYP1B1*2) and Ala119Ser (CYP1B1*2) polymorphisms of CYP1B1 in cases versus controls. No significant differences were observed for the distribution of variant genotypes-Leu432Val (CYP1B1*3) and Asn453Ser (CYP1B1*4), respectively. When the four SNPs were analyzed using a haplotype approach, SNPs at codon 48 (Arg48Gly) and codon 119 (Ala119Ser) exhibited complete linkage disequilibrium (LD) in all the cases and controls. Significant differences in the distribution of the two haplotypes (G-T-C-A and G-T-G-A) were observed both in the cases and in controls. Furthermore, our data indicates a several fold increase in risk in the cases who use tobacco (cigarette smoking or tobacco chewing) or alcohol with the variant genotypes of CYP1B1 (CYP1B1*2 and CYP1B1*3) suggesting the role of gene-environment interaction in the susceptibility to HNSCC.

Association of poor metabolizers of cytochrome P450 2C19 with head and neck cancer and poor treatment response.

A case-control study consisting of 300 patients and an equal number of healthy controls was carried out to investigate the association of polymorphism in cytochrome P450 2C19 (CYP2C19), which results in poor and extensive metabolizers (PMs and EMs) genotypes, with squamous cell carcinoma of head and neck (HNSCC) and treatment response in patients receiving combination of chemo-radiotherapy. A higher frequency of CYP2C19 2 variants was observed in the cases resulting in significantly higher risk to HNSCC (Ad OR 3.36, 95% CI 1.94-5.82, p-value<0.05). The PM genotype of CYP2C19 3 was also found to be slightly increased in the cases, though the increase in risk was not significant when analyzed by multivariate logistic regression model. Tobacco chewing amongst the cases resulted in almost 13-fold increase in the risk with CYP2C19 2 (OR: 12.39) and 3-fold with CYP2C19 3 genotype (OR: 2.90) when compared to the tobacco chewers amongst the controls. Likewise, cigarette smoking in the cases increased the risk approximately 9-fold and 3-fold with CYP2C19 2 (OR: 8.93) and CYP2C19 3 (OR: 2.18) genotypes respectively when compared to smokers amongst the controls. Similar increase in risk was associated with alcohol use amongst the cases carrying variant genotypes of CYP2C19 2 (OR: 7.75) or CYP2C19 3 (OR: 2.60), demonstrating the importance of gene-environment interaction in modifying susceptibility to HNSCC. Interestingly, patients with PMs of CYP2C19 (CYP2C19 2 and CYP2C19 3) exhibited little response to the respective chemotherapy than the patients carrying wild-type genotype demonstrating that functional enzyme deficiencies due to polymorphism in CYPs may not only be important in modifying the susceptibility to HNSCC but also in determining chemotherapeutic response.

Association of functionally important polymorphisms in cytochrome P4501B1 with lung cancer.

In the present study, genotype and haplotype frequencies of four polymorphisms of cytochrome P450 1B1 (CYP1B1) that cause amino acid changes (Arg-Gly at codon 48, Ala-Ser at codon 119, Leu-Val at 432 and Asn-Ser at codon 453) were studied in 200 patients suffering from lung cancer and equal number of controls. A significant difference was observed for the distribution of variant genotypes of CYP1B1Arg48Gly and Ala119Ser polymorphisms (CYP1B1*2) in cases when compared to the controls. No significant difference was observed for the distribution of variant genotypes of CYP1B1Leu432Val (CYP1B1*3) and CYP1B1Asn453Ser (CYP1B1*4) polymorphism. When the four SNPs were analyzed using a haplotype approach, SNPs at codon 48 (Arg48Gly) and codon 119 (Ala119Ser) exhibited complete linkage disequilibrium (LD) in all the cases and controls. Significant differences in the distribution of the three haplotypes (G-T-C-A, G-T-G-A and G-T-C-G) were observed in the cases when compared to controls. Tobacco use in the form of smoking as well as chewing was found to significantly increase the risk of lung cancer in patients by interacting with CYP1B1Ala119Ser genotypes demonstrating the role of gene-environment interaction in lung cancer. Further, the risk of lung cancer increased several fold in the patients carrying the genotype combinations of CYP1B1Ala119Ser and CYP1B1Leu432Val with GSTM1, a phase II enzyme suggesting the importance of gene-gene interactions in enhancing the susceptibility to lung cancer.

Association of genetic variability in enzymes metabolizing chemotherapeutic agents with treatment response in head and neck cancer cases.

AIM: The prevalence of genetic variants of thiopurine S-methyltransferse (TPMT) and dihydropyrimidine dehydrogenase (DPD) in healthy controls (500) and the treatment response in 500 cases of head and neck cancer of north Indian origin was studied. METHODS: Blood collected from all the subjects was used for isolation of DNA followed by genotyping studies. The cases received cisplatin and 5-fluorouracil (5-FU) or chemo-radiotherapy and treatment response was measured using WHO criteria. RESULTS: Low frequency of heterozygous mutant genotypes of TPMT*2 (2%), TPMT*3B (2.2%), TPMT*3C (4.6%), DPD IVS14+1G>A (3.6%) and G1601A (3%) was observed, although no homozygous mutants could be identified. Treatment response studies in cases receiving cisplatin and 5-FU or chemo-radiotherapy revealed that the number of nonresponders was higher in cases who carried variant genotypes of TPMT*3B (62.50%) or TPMT*3C (59.26%) or DPD IVS14+1G>A (61.90%). Likewise, the number of nonresponders was still higher in cases carrying combination of these genetic variants. Furthermore, the frequency of nonresponders was higher in cases who carried the variant genotypes of TPMT or DPD and were also tobacco users. CONCLUSIONS: Our data clearly show that TPMT and DPD genes are polymorphic in the north Indian population and may be important in determining the treatment response in cases. The data have also suggest tobacco may play an important role in determining the outcome of cancer therapy and there is an urgent need for assessment of drugs for their efficacy/toxicity in smokers compared to nonsmokers.

GSTT1, GSTM1 and GSTP1 genetic polymorphisms and interaction with tobacco, alcohol and occupational exposure in esophageal cancer patients from North India.

Glutathione S-transferases(GSTs) are detoxification enzymes that provide critical defense against carcinogens. Our hypothesis was that altered frequencies of GST genotypes and environmental exposures might be associated with increased susceptibility for the development of esophageal cancer. A total of 100 esophageal cancer patients and 137 age and gender matched healthy controls were analyzed for GST polymorphisms. Frequencies of GSTT1 null, GSTM1 null and GSTP1 genotypes did not differ between patients and controls. However, a two-fold risk was observed for GSTM1 null genotype in adenocarcinoma (OR(odds ratio) 2.1; 95% CI(confidence intervals)=0.53-8.6). Further, we used a case only design to study gene-environment interactions in esophageal cancer. In patients with smoking habits, GSTM1 null and GSTP1 ile/ile genotype were at higher risk for esophageal cancer (OR 1.5; 95% CI=0.50-4.4 and OR 1.3; 95% CI=0.40-3.5), respectively. A moderate risk for cancer was observed from alcohol usage along with GSTM1 null(OR 1.3; 95% CI=0.50-3.6) and GSTP1 val/val genotypes(OR 1.2; 95% CI=0.20-5.7). Interaction of GST genotypes with occupational exposure did not affect risk for esophageal cancer. These findings suggest that genetic polymorphisms of GSTT1, GSTM1, and GSTP1 are not associated with higher risk of esophageal cancer. However, interaction of smoking or alcohol with GSTM1 null or GSTP1 ile/ile moderately increases the risk for esophageal cancer in North Indian population.

Clinical Management of Head and Neck Cancer Cases: Role of Pharmacogenetics of CYP2 and GSTs.

Head and neck squamous cell carcinoma (HNSCC) describes a wide range of malignant tumors which originate in the upper aerodigestive tract and have a multifactorial origin involving both genetic and lifestyle risk factors. The clinical management of head and neck cancer involves surgery, radiotherapy, and chemotherapy. With the advances in treatment strategies for HNSCC, newer targeted therapies are adding to the progress already achieved in the multimodality management of patients although the problems of differences in drug response and adverse drug reactions are still grave concerns. Cancer pharmacogenomics has fast emerged as a new and promising field for the early identification of genetic markers that can predict drug response or toxicity. This could greatly help in identifying genetic markers useful for the selection of optimal drugs, dose, and treatment duration on an individual basis resulting in improved drug efficacy and decreased toxicity. This review focuses on the various treatment modalities available for the clinical management of HNSCC followed by a description of the contribution of genetic variations to chemotherapeutic toxicity and response. Furthermore, studies addressing the association of genetic variants of drug-metabolizing enzymes with treatment response in head and neck cancer are also discussed.

Gene-environment interactions in determining differences in genetic susceptibility to cancer in subsites of the head and neck.

Genetic differences in susceptibility to cancer in subsites of the head and neck were investigated in a case-control study involving 750 cases of cancers of the oral cavity, larynx, or pharynx, and an equal number of healthy controls. The prevalence of variant genotypes of cytochrome P450 (CYP) 1A1, 1B1, 2E1, or glutathione-S-transferase M1 (null) in cases suggests that polymorphisms in drug metabolizing enzymes (DMEs) modify cancer risk within subsites of the head and neck. Tobacco or alcohol use was found to increase the risk in cases of laryngeal, pharyngeal, or oral cavity cancers. Interaction between genetic variation in DMEs and tobacco smoke (or smoking) exposures conferred significant risk for laryngeal cancer. Likewise, strong associations of the polymorphic genotypes of DMEs with cases of pharyngeal and oral cavity cancer who were tobacco chewers or alcohol users demonstrate that gene-environment interactions may explain differences in genetic susceptibility for cancers of the oral cavity, larynx, and pharynx.

Association of polymorphism in cytochrome P450 2C9 with susceptibility to head and neck cancer and treatment outcome.

The present case-control study involving 750 cases and equal number of healthy controls investigates the association of polymorphism in cytochrome P450 2C9 (CYP2C9) with head and neck squamous cell carcinoma (HNSCC) and response in patients receiving chemotherapy or combination of radio-chemotherapy. The frequency of heterozygous or homozygous genotypes of CYP2C9*2 & CYP2C9*3, which leads to the poor metabolizer (PM) genotype was significantly higher in HNSCC cases when compared to the healthy controls resulting in significantly increased risk in the cases. Tobacco use in the form of tobacco smoking or tobacco chewing was found to increase the risk several fold in cases when compared to the non-tobacco users. Likewise, alcohol intake in cases with variant genotypes of CYP2C9*2 or CYP2C9*3 also significantly increased the HNSCC risk in cases when compared to non-alcohol users. Further, majority of the cases carrying variant alleles of both CYP2C9*2 or CYP2C9*3 were found to respond poorly to the chemotherapy or combination of radio-chemotherapy. The data suggests a significant association of the CYP2C9 polymorphism with HNSCC and treatment outcome.

Polymorphisms in drug-metabolizing enzymes and risk to head and neck cancer: evidence for gene-gene and gene-environment interaction.

A case-control study involving 750 cases with squamous-cell carcinoma of the head and neck (HNSCC) and an equal number of healthy controls was initiated to investigate the association of polymorphisms in the drug metabolizing genes cytochrome P450 1A1 (CYP1A1), CYP1B1, CYP2E1 and glutathione S-transferase M1 (GSTM1) with the risk of developing cancer. Attempts were also made to identify the role and nature of gene-gene and gene-environment interactions in modifying the susceptibility to HNSCC. Polymorphisms in drug metabolizing CYPs or GSTM1 showed modest associations with cancer risk. However, cases carrying haplotypes with variant alleles of both CYP1A1*2A and *2C or CYP1B1*2 and *3 or CYP2E1*5B and *6 were at significant risk of developing HNSCC. Likewise, cases carrying a combination of variant genotypes of CYPs and GSM1 (null) were at higher risk (up to 5-fold) of developing HNSCC. HNSCC risk also increased several-fold in cases carrying variant genotypes of CYPs who were regular tobacco smokers (8-18-fold), tobacco chewers (3-7-fold), or alcohol users (2-4-fold). Statistical analysis revealed a more than multiplicative interaction between combinations of the variant genotypes of CYPs and GSTM1 (null) and between variant genotypes and tobacco smoking or chewing or alcohol consumption, in both case-control and case-only designs. The data thus suggest that although polymorphisms in carcinogen-metabolizing CYPs may be a modest risk factor for developing HNSCC, gene-gene, and gene-environment interactions play a significant role in modifying the susceptibility to HNSCC.

Polymorphism Arg72Pro of p53 confers susceptibility to squamous cell carcinoma of lungs in a North Indian population.

The causes of lung cancer might be many, but genetic variation in the genes of carcinogen-metabolizing enzymes, tumor suppressor proteins, and/or DNA-repairing enzymes can also play a significant role in lung cancer susceptibility. The tumor suppressor protein p53 functions to induce cell cycle arrest, DNA repair, or apoptosis. Polymorphism in its gene can, therefore, play a significant role in cancer susceptibility. Present report evaluated the association of polymorphism in exon 4 Arg72Pro (G>C) of the p53 gene with lung cancer susceptibility using 175 cancer cases and 202 controls from the North Indian population. Binary logistic regression analysis revealed that the Pro72Pro genotype was significantly associated with increasing risk for lung cancer in younger age patients (≤55 years) (adjusted odds ratio [OR]=2.72, 95% confidence intervals [95% CI] 0.99-7.85, p<0.05). Histological stratification of lung cancer revealed that the Pro72Pro genotype was associated with higher risk for squamous cell carcinoma (OR=3.05, 95% CI 1.07-8.87, p<0.05). Genetic variation Arg72Pro of the p53 gene may contribute to higher risk of SCC of lung in the North Indian population.

Concurrent chemoradiation versus radiotherapy alone in cervical carcinoma: A randomized phase III trial.

AIM: Chemo-radiotherapy (CRT) is the standard of care for treating almost all cervical carcinoma patients on the basis of the National Cancer Institute (NCI) alert. The disease burden in developing countries is more advanced with poor general condition than in patients in the trials prompting the NCI alert. Therefore, practicing CRT as standard of care should be tested in these patients. METHODS: A randomized controlled trial was conducted comparing radiotherapy (RT) alone with CRT (cisplatin 40 mg/m(2) weekly × 5) in patients with localized stage Ib to IVa cervical carcinoma between September 2006 and December 2008. External beam RT was delivered using a telecobalt unit. This was followed by 12-18 Gy of brachytherapy. RESULTS: In total, 305 patients were recruited: RT alone (150) and CRT (155). The median follow up was 34 months. Locoregional relapse-free survival (LRFS) at 2 years was 55 and 54% for the RT and CRT group, respectively, with a median LRFS time of 27 and 30 months for the RT and CRT group, respectively, (P = 0.624). Overall survival (OS) at 2 years was 58 and 60%, with a median OS of 31 and 34 months for the RT and CRT group, respectively; (P = 0.9). The toxicity profile, both acute and late, were comparable in both groups; CONCLUSION: No improvement in outcome was seen with addition of cisplatin. In the Indian subcontinent where patients present at late stages with poor general condition and limited access to good supportive care, RT alone still remains a valid option.