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.
Yadav
Sunishtha S
SS
Developmental Toxicology Division, Indian Institute of Toxicology Research (Formerly Industrial Toxicology Research Centre), CSIR P.O. Box 80, M.G. Marg, Lucknow 226001, India.
Ruwali
Munindra
M
Shah
Parag P
PP
Mathur
Neeraj
N
Singh
Ram L
RL
Pant
Mohan C
MC
Parmar
Devendra
D
D000328:Adult; D000428:Alcohol Drinking / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000209:etiology / Q000235:genetics* / Q000628:therapy; D016022:Case-Control Studies; D003131:Combined Modality Therapy; D065731:Cytochrome P-450 CYP2C19; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000235:genetics* / Q000628:therapy; D006801:Humans; D007194:India; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D014030:Tobacco, Smokeless / Q000009:adverse effects
D000970:Antineoplastic Agents; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19