Association of Cytochrome P450 2D6 (Cyp2D6) Polymorphisms with Susceptibility to Head & Neck Squamous Cell Carcinoma & Treatment Response

Abstract

ABSTRACT Aim: The present study aimed to identify the poor metabolizers (PMs) genotype of CYP2D6 & their effect on treatment outcomes in HNSCC cases. Methods: This case-control study comprised 375 male cases with head and neck squamous cell carcinoma (HNSCC) and an equal number of healthy controls from the same ethnic group (Indo-European community) of North India. Patients having any concurrent illness with HNSCC and who defaulted during the treatment and whose expected survival were not more than 6 months were excluded from the study. Genomic DNA was isolated from blood samples collected from controls and patients and was studied by polymerase chain reaction-restriction fragment length polymorphism technique (PCR-RFLP). Patients were subjected to three cycles of neo-adjuvant chemotherapy, before concurrent chemotherapy with radiotherapy. Response was assessed using the WHO criteria. Results: A higher prevalence of heterozygous and homozygous genotypes of CYP2D6*4 & CYP2D6*10 polymorphism were found in the cases when compared with the controls. Adjustment of the data for age, cigarette smoking, and tobacco chewing and alcohol consumption revealed that the risk increased in the cases with heterozygous genotype (Adj. OR: 1.24; 95% CI: 0.85–1.80) or homozygous genotype (Adj. OR: 1.82; 95% CI: 0.90–3.68) of CYP2D6*4 polymorphism. Likewise, adjustment of the data for age, cigarette smoking, and tobacco chewing and alcohol consumption revealed that the risk continued to be significantly increased in the cases with heterozygous genotypes (Adj. OR: 2.18; 95% CI: 1.48–3.19) or homozygous genotypes (Adj. OR: 1.88; 95% CI: 1.13–3.14) of CYP2D6*10 polymorphism. Pharmacogenetic study revealed that the majority of the patients with variant CYP2D6*4 genotype were found to be non-responders (67.0%), while only 33% exhibited good response. Amongst PMs of CYP2D6*10 genotype only 32.9% responded to the treatment. Both these differences were found to be statistically significant. Conclusions: The findings demonstrate that polymorphisms (SNPs) in functional enzymes such as CYP2D6 enhance susceptibility to HNSCC and also determines chemotherapeutic response by worsening the drug metabolism and availability of the metabolites required for effective treatment. Disclosure: All authors have declared no conflicts of interest.