Interaction of cytochrome P450s with environmental risk factors increases their expression and risk to head and neck cancer.

To investigate the role of interaction of tobacco metabolizing polymorphic cytochrome P450s (CYPs) and glutathione S-transferase M1 (GSTM1) with environmental risk factors in modifying the susceptibility to head and neck squamous cell carcinoma (HNSCC), a case-control study with 1250 proven cases of HNSCC and equal number of healthy controls was planned. A small but significant increase in the risk to HNSCC (1-2 fold) in the cases with variant genotypes of CYPs (1A1 or 1B1 or 2E1) increased several folds (up to 13 fold) in regular tobacco or alcohol users. This several fold increase in risk could be due to more than multiplicative interaction observed between the risk genotypes of CYPs and tobacco or alcohol. A synergistic effect was also observed between tobacco as well as alcohol users among cases with risk genotypes of CYPs and GSTM1 that resulted in a further increase in risk (up to 29 fold) to HNSCC. Interestingly, the increase in the risk in tobacco users among cases with variant genotypes of CYPs or a combination of CYPs & GSTM1 (-) was associated with a higher mRNA expression of CYPs when compared to nontobacco users in controls with wild type of genotypes of CYPs & GSTM1. The data suggest that the interaction of genetic and environmental risk factors leads to increased expression of CYPs which may increase the levels of tobacco-derived carcinogens thereby modifying the risk to HNSCC.

Polymorphism in cytochrome P4502A6 reduces the risk to head and neck cancer and modifies the treatment outcome.

The present case-control study consisting of 1300 cases of head and neck squamous cell carcinoma (HNSCC) and the equal number of controls aimed to investigate the association of functionally important polymorphisms in cytochrome P4502A6 (CYP2A6*1B, CYP2A6*4C, CYP2A6*9-rs28399433) with HNSCC and the treatment response in cases receiving a combination of chemotherapy/radiotherapy (CT/RT). A significant decrease in risk to HNSCC was observed in the cases with deletion (CYP2A6*4B and CYP2A6*4C) or reduced activity genotypes (CYP2A6*9) of CYP2A6. This risk to HNSCC was further reduced significantly in tobacco users among the cases when compared to nontobacco users among the cases. The risk was also reduced to a slightly greater extent in alcohol users among the cases when compared to nonalcohol users among the cases. In contrast with decreased risk to HNSCC, almost half of the cases with variant genotypes of CYP2A6 (CYP2A6*1A/*4C+*1B/*4C+*4C/*4C and *9/*9) did not respond to the treatment. Likewise, the survival rate in cases receiving the treatment, after 55 months of follow-up was significantly lower in cases with deletion (6.3%) or reduced activity (11.9%) allele than in the cases with common alleles (41%). The present study has shown that CYP2A6 polymorphism significantly reduces the risk to HNSCC. Our data further suggested that CYP2A6 polymorphism may worsen the treatment outcome in the cases receiving CT/RT.

Towards a comprehensive safety understanding of granulocyte-colony stimulating factor biosimilars in treating chemotherapy associated febrile neutropenia: Trends from decades of data.

Filgrastim, a biopharmaceutical listed on WHO model list of essential medicines, was approved in USA in 1991 for patients with non-myeloid malignancies associated with severe neutropenia and fever. Several filgrastim biosimilars have now been approved in USA, Europe and elsewhere since 2008, based on the reference product which has lost patent exclusivity; however their immunogenicity and safety is controversial. We conducted a retrospective, post market study between 1991 and May 2018 using VigiBase®. The study included all adverse events with case reports ≥150. Overall, 11,183 adverse drugs reaction reports were identified during observation period; of which 5764; 51.5% reports concerned to Neupogen®, the originator, and rest consists of Leucostim® (N = 680), Zarzio® (N = 622), Grasin® (N = 545), Nivestim® (N = 359) and Tevagrastim® (N = 152) biosimilars. When compared with the originator, Grasin® was associated with higher reporting of pyrexia (11.5% vs 7.9%, ROR 1.52, IC025 1.12), myalgia (37% vs 2.2%, ROR 25.94, IC025 2.11) and back pain (11.3% vs 4%, ROR 3.09, IC025 2.32). Zarzio® was associated with increased reporting of arthralgia (4.5% vs 2.9%, ROR 1.59, IC025 1.25) and neutropenia (11.4% vs 4%, ROR 2.59, IC025 3.07). Bone pain was reported more often with Nivestim® (14.4% vs 8.3%, ROR 1.87, IC025 5.30). Drug ineffectiveness was reported in cases with Zarzio® (35.9%), Nivestim® (19.4%) and Tevagrastim® (42.2%). Authors observed significant differences among originator and biosimilars in particular to efficacy, adverse events reported and time to onset of occurrences. Large epidemiologic studies are needed to further confirm these finding and provide additional insights.

Interaction of glutathione-s-transferase genotypes with environmental risk factors in determining susceptibility to head and neck cancer and treatment response and survival outcome.

The present case-control study aimed to investigate the role of interaction of glutathione-s-transferase (GST) genotypes with environmental risk factors in determining susceptibility to head and neck squamous cell carcinoma (HNSCC) involving 1,250 cases and equal number of healthy controls. An increase in the risk of HNSCC and its subsites (larynx, pharynx, and oral cavity) was observed among the cases with null genotypes of GSTM1 (odds ratio [OR] = 1.87) or GSTT1 (OR = 1.39) while reduced risk (OR = 0.81) was observed the cases with variant genotype of GSTP1. Tobacco use in the form of smoking or chewing interacted multiplicatively with GSTM1 or GSTT1 to increase the risk several folds (3-10 folds) in HNSCC and its subsites. Alcohol use also increased the risk (2-3 folds) to HNSCC and its subsites in cases with null or variant genotypes of GSTs, though this risk was of lesser magnitude when compared to the tobacco users. A synergistic effect of both, tobacco smoking and alcohol drinking, led to several folds (25-folds) increased risk to HNSCC among the cases with null genotype of GSTM1 and GSTT1 when compared to nonsmokers and nondrinkers with wild genotype of GSTM1 and GSTT1 in controls. Furthermore, cases with variant genotypes of GSTP1 (Val/Val) showed superior treatment response with improved survival rate and lower risk of death when compared to the patients with wild type genotype (Ile/Ile). The data suggest that though polymorphism in GSTs may be a modest risk factor for determining HNSCC risk, gene-environment interactions significantly modify the susceptibility to HNSCC by several folds.

Validation of gene expression profiles of candidate genes using low density array in peripheral blood of tobacco consuming head and neck cancer patients and auto/taxi drivers with preneoplastic lesions.

TaqMan Low-Density Array (TLDA) based Real-Time PCR (RT-PCR) of selected genes showed increased expression of polycyclic aromatic hydrocarbons (PAHs) metabolizing cytochrome P450s (CYPs), glutathione S-transferases (GSTs) and associated transcription factors in biopsy and peripheral blood samples isolated from head and neck squamous cell carcinoma (HNSCC) patients when compared to the controls. The genes involved in DNA repair, signal transduction pathway, EMT pathway, apoptosis, and cell adhesion/motility were found to be altered in both peripheral blood and biopsy samples of HNSCC patients. Transcription profiles in blood isolated from auto/taxi drivers, with pre-neoplastic lesions and history of tobacco use, also showed similar alterations. The present TLDA data thus demonstrates that low-density array of selected genes in peripheral blood has the potential to be used as a surrogate for providing insight into cancer progression pathways and possibly as an early biomarker for monitoring tobacco induced HNSCC.

Similarities in mRNA expression of peripheral blood drug metabolizing enzymes and cancer marker genes with biopsy samples of head and neck cancer patients.

Purpose: To develop peripheral blood mRNA expression profiles of drug metabolizing enzymes (DMEs) as a surrogate to monitor tobacco induced head and neck squamous cell carcinoma (HNSCC), attempts were made to investigate (i) similarities in alterations with the cancer marker genes in biopsy samples and (ii) if alterations similar to that seen in biopsy samples are reflected in peripheral blood. Methods: Total RNA from eight soft gingival tissues and eight biopsy samples of HNSCC patients and total DNA and RNA from blood of healthy controls (n = 150) and HNSCC patients (n = 150) was processed for expression and genotyping studies. Blood from patients receiving chemo-radiotherapy was processed for follow-up study. Results: qRT-PCR revealed significant increase in mRNA expression of DMEs in biopsy and blood samples of HNSCC patients when compared to controls. Similar alterations were observed in cancer marker genes in these samples. Patients with variant genotypes of DMEs showed greater magnitude of alterations in mRNA expression when compared to wild type controls. Responders of chemo-radiotherapy showed significant decline in induction of mRNA expression of DMEs and cancer marker genes Conclusions: The data suggest that peripheral blood expression profiles could be used to monitor tobacco-induced HNSCC as well as the treatment response.

To investigate the affiliation of XRCC-1 Gene Arg194Trp polymorphism in alcohol and tobacco substance users and loco-regionally progressed Laryngeal squamous cell carcinoma.

OBJECTIVES: The correlation of XRCC-1 Gene Arg194Trp polymorphism with alcohol and tobacco substance user and with loco-regionally progressed squamous cell cancer of the larynx (LSCC) was assessed in this research study. The result of this research study is described herein. MATERIAL AND METHODS: A tertiary hospital-based observational case-control research was carried out. DNA segregation and Genotype examination were done from the blood sample of the control group and cases to know the correlation between XRCC-1 gene polymorphism with loco-regionally progressed LSCC and with hazard factors tobacco and alcohol. RESULTS: In the cases, the existence of DNA repair XRCC-1 gene polymorphic variants (Hetero CT and Mutant TT) was recognizable in contrary to the control group arm. The XRCC-1 gene polymorphic hetero (CT) genotype (O.R-1.96; 95% C.I: 1.23-3.13; P < 0.004) and mutant (TT) genotype variants (O.R-1.95; 95% C.I: 0.59-6.44; P = 0.27) was correlated with access hazard of loco-regionally progressed LSCC, and its statistically convincing for polymorphic hetero (CT) variant. The data were adapted for the age of the patients and control group, circadian alcohol intake, tobacco chewing habits, and the tobacco smoking habits during application of multivariate logistic regression. Its apparent that the hazard is amalgamated with hetero (CT) genotype variant (O.R- 1.67; 95% C.I: 0.98-2.82; P = 0.05) and mutant (TT) genotype variant (O.R- 1.62; 95% C.I: 0.88-2.78; P = 0.11) and its statistically convincing for polymorphic hetero (CT) genotype variant. Cases with the record of substance use (alcohol and tobacco) have an abundance of XRCC-1 hetero (CT) and mutant (TT) genotype variants in allegory to control group. Increased hazard is related with XRCC-1 hetero (CT) variant in smokers (O.R 3.28; 95% C.I: 1.45-7.41; P = 0.004), in tobacco chewers (O.R-3.79; 95% C.I: 1.87-7.71; P = 0.0002), and in alcohol consumers (O.R- 4.24; 95% C.I: 2.21-8.15; P= <0.0001) which is statistically significant. CONCLUSION: This research investigation demonstrates the correlation of XRCC-1 polymorphic hetero genotype (CT) & mutant genotype (TT) variants as hazard factor in loco-regionally progressed LSCC. Cases with the record of alcohol intake habits, tobacco smoking and chewing habits and XRCC-1 hetero genotype (CT) variant have statistically increased the hazard of loco-regionally progressed LSCC, which demonstrate the role of gene-ecological interconnection in modifying the vulnerability of loco-regionally progressed LSCC.

Association of cytochrome P450 1B1 haplotypes with head and neck cancer risk.

Genetic polymorphisms have been reported in several cytochrome P450 (CYP) genes, including CYP1B1 which metabolically activates procarcinogens present in tobacco to carcinogenic intermediates. This study used a case-control approach in North Indian population to determine associations between genetic variants in CYP1B1 and risk of Head and Neck Squamous Cell Carcinoma (HNSCC). We examined the genotype and haplotype frequencies at various single-nucleotide polymorphisms (SNPs), including SNPs previously reported in the promoter region and intron 1 of CYP1B1 in Caucasians. Using cycle sequencing, 9 SNPs were identified in the promoter region, intron 1, and exons 2 and 3. Haplotype analysis revealed that 5 SNPs (those in the promoter region, intron, and Arg48Gly and Ala119Ser in exon 2) were in strong linkage disequilibrium (LD). Cases with the T-A-T-G-T haplotype were significantly associated with increased risk of HNSCC. Interestingly, qRT-PCR studies revealed a significant increase in mRNA expression of CYP1B1 in peripheral blood isolated from cases with the T-A-T-G-T haplotype compared with cases with the C-G-C-C-G haplotype, and in cases compared to controls for both main haplotypes. The data thus provide evidence that CYP1B1 haplotypes could be more effective in predicting HNSCC risk. Environ. Mol. Mutagen. 58:443-450, 2017. © 2017 Wiley Periodicals, Inc.

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.