GSTM1 null and GSTT1 null: predictors of cisplatin-caused acute ototoxicity measured by DPOAEs

Abstract

Preventing the ototoxicity caused by cisplatin is a major issue yet to be overcome. Useful preventive treatments will soon be available. Consequently, the next step is to filter out those patients who are more prone to develop ototoxicity. The aim of this study was to prospectively evaluate potential predictive markers of acute ototoxicity as determined by measures of distortion product otoacoustic emissions (DPOAEs). A total of 118 patients from our previous DPOAE analysis were put under evaluation. Ototoxic cases were divided according to unilateral (n = 45) or bilateral (n = 23) involvement. The clinicopathological characteristics, hearing test results, germline GSTT1, GSTM1, and GSTP1 polymorphisms, and common laboratory parameters were included in the new analysis. Univariate and multivariate statistical tests were applied. According to multivariate logistic regression, the only independent predictor of unilateral ototoxicity (vs. non-affected) was a GSTM1 null genotype (OR = 4.52; 95%CI = 1.3-16.3), while for bilateral damage, the GSTT1 null genotype (OR = 4.76; 1.4-16) was a predictor. The higher starting serum urea level was characteristic of bilateral ototoxicity; however, the only independent marker of bilateral (vs. unilateral) ototoxicity was the presence of GSTT1 null genotype (OR = 2.44; 1.23-4.85). Different processes, involving the GSTM1 and GSTT1 genotypes, respectively, govern the development of acute unilateral and bilateral ototoxicities. Further research is needed to clarify these processes. Based on the above findings, patients whom are at risk may be selected for otoprotective therapies. Key messages & The acute ototoxicity was determined by DPOAE in 118 testicular cancer patients. & GSTM1 null was the only marker of unilateral ototoxicity (vs. non-affected). & The only marker of bilateral hearing loss (vs. non-affected) was the GSTT1 null. & GSTT1 null was also the marker of bilateral vs. unilateral ototoxicity. & A high-risk group may be selected for new, individualized otoprotective treatment.

Gstm1/Gstt1 is essential for reducing cisplatin ototoxicity in CBA/CaJ mice

“…Consistent with our results, GSTM1 and GSTT1 may be selected as predictive markers for cisplatin‐induced acute ototoxicity in testicular cancer patients receiving cisplatin‐based chemotherapy 22 . In children with medulloblastoma receiving cisplatin therapy, GSTM1 and GSTT1 polymorphisms may also predict negative effects, such as cognitive problems and ototoxicity 23 .…”

“…According to a recent study, Gsta4 deficiency causes more severe hearing loss in female mice than in male mice after cisplatin treatment, and GSTA4‐mediated cisplatin ototoxicity decreases in female mice with 4‐hydroxynonenal (4‐HNE) elimination from the cochleae 21 . In addition to GSTA4 deficiency, GSTM1 and GSTT1 polymorphisms have been linked to the susceptibility to ototoxicity in patients undergoing cisplatin‐based chemotherapy 22,23 . In humans, deletion polymorphisms of the genes encoding GSTM1 and GSTT1 are widespread, and they are clinically significant as they lead to differences in metabolism of exogenous active substances and disease susceptibility among different individuals 24–29 .…”

Prevención y diagnóstico precoz de la sordera por ototóxicos Recomendaciones CODEPEH 2020

“…Tras analizar los polimorfismos GSTT1, GSTM1 y GSTP1, concluyen que los genotipos GSTM1null y GSTT1null demostraron ser marcadores independientes de ototoxicidad aguda uni y bilateral, respectivamente. La identificación a priori de este grupo de alto riesgo puede servir como base para una mejor definición de un tratamiento individualizado y el uso dirigido de nuevos fármacos otoprotectores (Budai et al, 2020).…”

Ototoxicity as a Side-Effect of Drugs: Literature Review

“…All these drugs show ototoxic sideeffects. However, cisplatin is the oldest drug in this group; it is the most commonly prescribed platinum drug, but is also the most ototoxic [42,129,130]. It is a well-known chemotherapeutic agent used in both children and adults, primarily for the treatment of malignant neoplasms: osteomyosarcoma, germ cell, liver, immature neuroblastoma, embryonic tumor, head and neck cancer, and some cancers of the central nervous system [43].…”