Association between long-term neuro-toxicities in testicular cancer survivors and polymorphisms in glutathione-s-transferase-P1 and -M1, a retrospective cross sectional study.

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Oldenburg J, Kraggerud SM, Brydoy M, Cvancarova M, Lothe RA, Fossa SD

Association between long-term neuro-toxicities in testicular cancer survivors and polymorphisms in glutathione-s-transferase-P1 and -M1, a retrospective cross sectional study.

J Transl Med. 2007 Dec 27;5:70.

PubMed ID

18162130 [ View in PubMed

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Abstract

BACKGROUND: To assess the impact of polymorphisms in Glutathione S-transferase (GST) -P1, -M1, and -T1 on self-reported chemotherapy-induced long-term toxicities in testicular cancer survivors (TCSs). METHODS: A total of 238 TCSs, who had received cisplatin-based chemotherapy at median twelve years earlier, had participated in a long-term follow-up survey which assessed the prevalence of self-reported paresthesias in fingers/toes, Raynaud-like phenomena in fingers/toes, tinnitus, and hearing impairment. From all TCSs lymphocyte-derived DNA was analyzed for the functional A-->G polymorphism at bp 304 in GSTP1, and deletions in GST-M1 and GST-T1. Evaluation of associations between GST polymorphisms and self-reported toxicities included adjustment for prior treatment. RESULTS: All six evaluated toxicities were significantly associated with the cumulative dose of cisplatin and/or bleomycin. Compared to TCSs with either GSTP1-AG or GSTP1-AA, the 37 TCSs with the genotype GSTP1-GG, were significantly less bothered by paresthesias in fingers and toes (p = 0.039, OR 0.46 [0.22-0.96] and p = 0.023, OR 0.42 [0.20-0.88], respectively), and tinnitus (p = 0.008, OR 0.33 [0.14-0.74]). Furthermore, absence of functional GSTM1 protected against hearing impairment (p = 0.025, OR 1.81 [1.08-3.03]). CONCLUSION: In TCSs long-term self-reported chemotherapy-induced toxicities are associated with functional polymorphisms in GSTP1 and GSTM1. Hypothetically, absence of GST-M1 leaves more glutathione as substrate for the co-expressed GST-P1. Also intracellular inactivation of pro-apoptotic mediators represents a possible explanation of our findings. Genotyping of these GSTs might be a welcomed step towards a more individualized treatment of patients with metastatic testicular cancer.

DrugBank Data that Cites this Article

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Cisplatin	Glutathione S-transferase Mu 1 Gene symbol: GSTM1 UniProt: P09488	GSTM1	Not Available	presence of functional GSTM1	ADR Directly Studied	Patients with this genotype have increased risk of ototoxicity with [durg: cisplatin].	Details
Cisplatin	Glutathione S-transferase P Gene symbol: GSTP1 UniProt: P09211	---	(A;G) / (G;G)	Not Available	ADR Directly Studied	Patients with this genotype have increased risk of ototoxicity with [durg: cisplatin].	Details