Polymorphic variants of drug-metabolizing enzymes alter the risk and survival of oral cancer patients
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ORIGINAL ARTICLE
Polymorphic variants of drug‑metabolizing enzymes alter the risk and survival of oral cancer patients Sarika Daripally1,2 · Kiranmayi Peddi3 Received: 4 May 2020 / Accepted: 28 October 2020 © King Abdulaziz City for Science and Technology 2020
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 CYP2D6*4 · CYP3A5*3 · SULT1A1*2 · Tongue cancer · Buccal mucosa cancer · 5-Year cumulative survival
Introduction Cytochrome P450 enzymes, CYP3A4/5, and CYP2D6 play a predominant role in the metabolism of drugs. The CYP3A4/5 and CYP2D6 metabolize 50% (Depaz et al. 2013) and 25% (Gaedigk et al. 2016) of drugs, respectively, Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13205-020-02526-5) contains supplementary material, which is available to authorized users. * Kiranmayi Peddi [email protected]; [email protected] 1
Basavatarakam Indo-American Cancer Hospital and Research Institute, Hyderabad, Telangana 500034, India
2
Acharya Nagarjuna University, Guntur, Andhra Pradesh 522210, India
3
Department of Biochemistry, Acharya Nagarjuna University, Guntur, Andhra Pradesh 522210, India
that are used both for common ailments and specific diseases like cancer (Zanger and Schwab 2013). Interestingly, these CYPs also activate pro-carcinogens to carcinogens present in tobacco which is a known risk factor for oral cancer (OC) (J
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