GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms in outcomes of head and neck squamous cell carcinoma patients treated with cisplatin chemoradiation

Eder C Pincinato,Guilherme A S Nogueira,Fernanda V Mariano,Luciane Calonga,Cláudia Coutinho-Camillo,Carmen S P Lima,João M C Altemani,Anna P L Costa,Tathiane R P Lima,Celso D Ramos,Carlos T Chone,Ericka F D Costa,Albina M A M Altemani,Leisa Lopes-Aguiar,Marília B Visacri,Gustavo J Lourenço,Patrícia Moriel

doi:10.1038/s41598-019-45808-6

Abstract

Cisplatin (CDDP) combined with radiotherapy (RT) is employed in head and neck squamous cell carcinoma (HNSCC) with variable toxicities and clinical response. Glutathione S-transferases (GSTs) participate in CDDP excretion from cells, and genes encoding GSTs, GSTM1, GSTT1and GSTP1, are polymorphic in humans. This prospective study aimed to evaluate the roles of GSTM1, GSTT1, and GSTP1 Ile105Val polymorphisms in outcomes of HNSCC patients treated with CDDP chemoradiation. Ninety patients were genotyped by multiplex PCR. Urinary CDDP measurements were performed by HPLC. Treatment side effects and response were analysed by conventional criteria. Patients with GSTT1 genes showed 7.23- and 5.37-fold higher likelihood of presenting vomiting and ototoxicity, lower glomerular filtration rate (GFR), and lower elimination of CDDP in urine relative to patients with deleted genes. Patients harbouring the GSTP1 IleVal or ValVal genotypes showed 4.28-fold higher likelihood of presenting grade 2 or 3 vomiting and lower GFR with treatment than those harbouring the IleIle genotype. In multivariate Cox analysis, patients with the GSTP1 105ValVal genotype had 3.87 more chance of presenting disease progression than those with the IleIle or IleVal genotype (p < 0.01). Our findings provide preliminary evidence that inherited abnormalities in CDDP metabolism, related to GSTT1 and GSTP1 Ile105Val polymorphisms, alter outcomes of HNSCC patients treated with CDDP and RT.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is a common cancer affecting humans and is responsible for around 600,000 cases and 350,000 tumour-related deaths worldwide each year[1]
The GSTM1, GSTT1, and/or GSTP1 Ile105Val polymorphisms were associated with variable survival in head and neck squamous cell carcinoma (HNSCC) patients treated with CDDP chemoradiation[15] or RT16
Considering the limited number of studies that investigated these genes, we conducted this prospective study to determine whether the GSTM1, GSTT1, and GSTP1 Ile105Val polymorphisms alter toxicity, response rate, and survival in HNSCC patients treated with CDDP and RT

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is a common cancer affecting humans and is responsible for around 600,000 cases and 350,000 tumour-related deaths worldwide each year[1]. HNSCC patients with similar clinicopathological aspects are expected to present variable toxicity, tumour regression, and survival following treatment with CDDP-based chemoradiation[8]. A few previous publications associated GSTM1, GSTT1, and/or GSTP1 Ile105Val polymorphisms with variable toxicities in HNSCC patients treated with CDDP and RT12–14.

Results

Conclusion