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


CONCLUSIONS
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.
Oldenburg
Jan
J
Department of Clinical Cancer Research, The Norwegian Radiumhospital, Oslo, Norway. janolde@ulrik.uio.no
Kraggerud
Sigrid M
SM
Brydøy
Marianne
M
Cvancarova
Milada
M
Lothe
Ragnhild A
RA
Fossa
Sophie D
SD
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity*; D003430:Cross-Sectional Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D012189:Retrospective Studies; D017741:Survivors; D013736:Testicular Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*
D000970:Antineoplastic Agents; D002945:Cisplatin; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase