Table 1.
Results of Published Studies in Cisplatin Pharmacogenomics Using Candidate Gene Approach
| Gene/Protein | Summary of Results |
|---|---|
| Megalin | Selected for candidate gene approach because it is highly expressed in renal proximal tubular cells and marginal cells of the inner ear. Also associated with the uptake of ototoxic aminoglycosides.46 |
| GSTs | Animal studies suggest GSTs are found in the cochlea and have a role in protection from ototoxicity. The GSTM1, GSTT1, and GSTP1 genes are polymorphic in humans, and nonfunctional variants are commonly found in whites.47 |
| TPMT, COMT | Two cohorts (identified through the Canadian Pharmacogenomics Network for Drug Safety) were evaluated for cisplatin toxicity.42 They used a gene chip composed of variants in 220 drug metabolism genes and found that genetic variants of TPMT (odds ratio, 17) and COMT (odds ratio, 5.5) were significantly associated with cisplatin-induced hearing loss. The combination of TPMT and COMT genotypes could be used as a clinical test to identify those who will have cisplatin-induced deafness with a positive predictive value of 92.9% and a negative predictive value of 48.6%.42 Mechanisms of toxicity include increased efficiency of cisplatin cross-linking, as well as a possible role of the methionine pathway through a common substrate, S-adenosylmethionine.42 |
| ERCC1, ERCC2 | ERCC1 encodes an excision repair enzyme involved in platinum DNA adduct repair.48 Two common single nucleotide polymorphisms in ERCC1 are correlated with an increased risk of both toxicity and survival in adults with non–small-cell lung tumors.49,50 |
| Mitochondrial gene mutations | No studies have been performed that have evaluated for associations between mitochondrial gene mutations and cisplatin-induced hearing loss. Aminoglycoside-induced deafness is thought to be associated with mutations in the mitochondrial 12S ribosomal RNA gene.51–53 |
Abbreviations: COMT, catechol-O-methyltransferase; ERCC1, excision repair cross-complementation group 1; ERCC2, excision repair cross-complementation group 2; GST, glutathione-S-transferase; TPMT, thiopurine S-methyltransferase.