Analysis of CYP2E1, ABCB1, ABCC2, OCT2 and MATE1 gene polymorphisms in the main cisplatin-mediated toxicity in the treatment of head and neck cancer

Author(s)

Maria Aparecida Cursino

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2022-02-14

Examining board members

Patricia Moriel; Cláudia Vianna Maurer Morelli; Mauricio Wesley Perroud Junior; Leonardo Régis Leira Pereira; Luis Antonio Salazar Navarrete

• Advisor: Patricia Moriel

Abstract

Head and neck cancer (HNC) is the set of malignant tumours located in the upper aerodigestive tract and the therapy is based on radiotherapy concomitant with high-dose cisplatin chemotherapy, which is limited by severe toxicities. Regarding cisplatin-mediated toxicity, mainly nephrotoxicity, there are considerable interindividual differences. Several aspects are considered to explain the different grades of toxicities and outcomes of the same treatment, and in this scenario, pharmacogenetics stands out. Genetic causes may include polymorphisms that affect the pharmacokinetics of cisplatin. Once traditional biomarkers of toxicity have low sensitivity and specificity, the aim of this study was to evaluate the relationship of genetic polymorphisms with the presence and severity of toxicities induced by cisplatin treatment in patients with HNC, to identify possible predictive biomarkers of these. Therefore, this is an observational analytical cohort study, with prospective and consecutive sampling strategy. Blood samples were collected from patients with HNC treated at the Clinical Oncology Outpatient Clinic of "HC-UNICAMP" (CAAE 69402017.1.0000.5404), before (baseline) and after cisplatin administration (80-100 mg/m2). Toxicities were graded according to Common Terminology Criteria for Adverse Events v4.0. Patients were genotyped for 13 polymorphisms in 5 target genes of cytochrome P450 (CYP2E1), ABC family transporters (ABCB1 and ABCC2) and OCT2 and MATE1 renal transporters, by qPCR using Taqman probes. Statistical associations were performed by SPSS v.27, considering p<0.05. Ninety-five patients (58.00±7.71 years) were included, 90.53% of whom were male. Nephrotoxicity, observed by the reduction in creatinine clearance, was highly prevalent during the first cycle of cisplatin, affecting 40.0% of patients in grades >2 (4.44% with grades between 3 and 4), accompanied by ionic imbalances, even with intense prophylactic hydration. Hematologic toxicities were observed with grade 3 and 4 of leukopenia, lymphopenia, and neutropenia. No grades above 3 of nausea and vomiting were observed. No hepatic parameter presented grades above 2. The allele frequencies observed are significantly different from those described in other populations, which points the need for robust genetic panels of this population. Correlations were observed between the SNPs of the CYP2E1 (rs3813865), ABCC2 (rs2032582) and ABCC2 (rs3740066 and rs717620) genes with cisplatin-mediated toxicities. On multivariate analysis, the rs3813865 variant allele was associated with higher odds of hypomagnesemia over grade 1 (p=0.033, OR=0.067). The rs717620 variant allele was associated with higher odds of neutropenia over grade 1 (p=0.040, OR=0.261). The rs2032582 wild type allele was associated with hyponatremia in grades above 1 (p=0.045, OR=3.398). The wild type allele of rs3740066 was associated with increase in serum creatinine with grades over 1 (p=0.010, OR=31.18). Therefore, this study identified SNPs as potential predictors of toxicity, which could contribute to the personalization of medicine, since cisplatin remains the first-line chemotherapy for various tumours and highlighted cisplatin-induced nephrotoxicity and the need for new genetic biomarkers to be validated (AU)

• FAPESP's process: 17/17245-7 - Polymorphism analysis of the CYP2E1, ABCB1, ABCC2, OCT2 and MATE1 genes involved in the major adverse effects of cisplatin treatment of the Head and Neck Cancer
• Grantee: Maria Aparecida Cursino
• Support Opportunities: Scholarships in Brazil - Doctorate