Polymorphic variants of drug-metabolizing enzymes alter the risk and survival of oral cancer patients

Abstract

The present study investigated the prevalence of CYP2D6*4, CYP3A5*3 and SULT1A1*2, using PCR-RFLP, in normal and oral cancer (OC) patients that were stratified by OC subtype and gender. The risk of cancer, 5-year cumulative survival and hazard's ratio (HR) with respect to risk factors and clinical factors were estimated using Fisher's exact test, Kaplan-Meier analysis, and Cox proportional hazards models. CYP2D6*4 'GA' lowered the risk of buccal mucosa cancer (BMC) in males (OR = 0.37), whereas, 'G' allele of CYP3A5*3 increased risk of tongue cancer (TC) (OR = 1.67). SULT1A1*2 'GA' increased the risk of TC (OR = 2.36) and BMC (OR = 3.25) in females. The 5-year survival of the patients depended on factors like age, lymphovascular spread (LVS), perinodal spread (PNS), recurrence, tobacco, and alcohol. CYP3A5*3 'AG' and 'GG' had decreased the hazard ratio (HR) for BMC females when inflammatory infiltrate alone or along with other covariates, LVS, PNI, PNS, metastasis, recurrence, and relapse was adjusted. Similarly, CYP3A5*3 'AG' decreased the risk of death (HR = 0.05) when the grade was adjusted. SULT1A1*2 'GA' had decreased HR for TC males (HR = 0.08) after adjusting for inflammatory infiltrate, LVS, perineural invasion (PNI), PNS, metastasis, recurrence, and relapse. Further, our bioinformatics study revealed the presence of a CpG island within the CYP2D6 and a CTCF binding site upstream of CYP2D6. Interestingly, three CpG islands and two CTCF binding sites were also identified near the SULT1A1. In conclusion, the SNPs altered risk and survival of BMC and TC differentially in a gender specified manner, that varied with clinical and risk factors.

Keywords: 5-Year cumulative survival; Buccal mucosa cancer; CYP2D6*4; CYP3A5*3; SULT1A1*2; Tongue cancer.

Fig. 1

Kaplan–Meier 5 year cumulative survival analysis of Wild type vs Mutant genotypes in oral cancer patients, stratified into tongue cancer (TC) and buccal mucosa cancer (BMC), gender, age groups of ≤ 50 years and > 50 years, tobacco chewing habit and CYP3A5*3 or SULT1A1*2. a BMC females aged ≤ 50 years and carriers of CYP3A5*3 (AA vs AG, AA vs GG); b TC females aged > 50 years and carriers of CYP3A5*3 (AA vs GG); c BMC males aged > 50 years and carriers of CYP3A5*3 (AA vs GG); d TC females who were tobacco chewers and carriers of SULT1A1*2 (GG vs GA)

Fig. 2

Kaplan–Meier 5 year cumulative survival analysis of Wild type vs Mutant genotypes in oral cancer patients, stratified into tongue cancer (TC) and buccal mucosa cancer (BMC), gender and CYP2D6*4, CYP3A5*3 or SULT1A1*2 with clinical factors. a TC females with high inflammatory infiltrate and carriers of CYP2D6*4 (GG vs GA); b BMC females with grade 1 tumour and carriers of CYP3A5*3 (AA vs AG); c BMC males with mild inflammatory infiltrate and carriers of CYP3A5*3 (AA vs GG); d BMC females with moderate inflammatory infiltrate and carriers of CYP3A5*3 (AA vs GG); e TC females with high inflammatory infiltrate and carriers of CYP3A5*3 (AA vs GG); f TC males with PNS and carriers of SULT1A1*2 (GG vs GA)