TPMT, COMT and ACYP2 genetic variants in paediatric cancer patients with cisplatin-induced ototoxicity.

OBJECTIVES: Cisplatin ototoxicity affects 42-88% of treated children. Catechol-O-methyltransferase (COMT), thiopurine methyltransferase (TPMT) and AYCP2 genetic variants have been associated with ototoxicity, but the findings have been contradictory. The aims of the study were as follows: (a) to investigate these associations in a carefully phenotyped cohort of UK children and (b) to perform a systematic review and meta-analysis. METHODS: We recruited 149 children from seven UK centres using a retrospective cohort study design. All participants were clinically phenotyped carefully. Genotyping was performed for one ACYP2 (rs1872328), three TPMT (rs12201199, rs1142345 and rs1800460) and two COMT (rs4646316 and rs9332377) variants. RESULTS: For CTCAE grading, hearing loss was present in 91/120 (75.8%; worst ear) and 79/120 (65.8%; better ear). Using Chang grading, hearing loss was diagnosed in 85/119 (71.4%; worst ear) versus 75/119 (63.0%; better ear). No TPMT or COMT single-nucleotide polymorphisms (SNPs) were associated with ototoxicity. ACYP2 SNP rs1872328 was associated with ototoxicity (P=0.027; worst ear). Meta-analysis of our data with that reported in previous studies showed the pooled odds ratio (OR) to be statistically significant for both the COMT SNP rs4646316 (OR: 1.50; 95% confidence interval: 1.15-1.95) and the ACYP2 SNP rs1872328 (OR: 5.91; 95% confidence interval: 1.51-23.16). CONCLUSION: We showed an association between the ACYP2 polymorphism and cisplatin-induced ototoxicity, but not with the TPMT and COMT. A meta-analysis was statistically significant for both the COMT rs4646316 and the ACYP2 rs1872328 SNPs. Grading the hearing of children with asymmetric hearing loss requires additional clarification.

The hOCT1 SNPs M420del and M408V alter imatinib uptake and M420del modifies clinical outcome in imatinib-treated chronic myeloid leukemia.

Although the prognosis of chronic myeloid leukemia (CML) patients treated with imatinib is good, many fail to develop an optimal response or lose one. This heterogeneity could be attributed to the presence of human organic cation transporter-1 (hOCT1) single nucleotide polymorphisms (SNPs). In the present study, we analyzed the effect of 23 hOCT1 SNPs on imatinib treatment outcome in newly diagnosed CML patients using MassARRAY sequencing and pyrosequencing. The only SNP associated with outcome was M420del (rs35191146), with patients with the M420del demonstrating an increased probability of imatinib treatment failure. In CML cell lines transfected with M420del and/or M408V, M420del significantly decreased imatinib uptake, but this effect was countered if the M408V (rs628031) SNP was also present. A similar effect was seen for the uptake of the hOCT1 substrates TEA(+) and ASP(+). Finally, apparent hOCT1 mRNA levels were studied using both our earlier primers covering the M420del and another set that did not. Different mRNA expression was observed, explaining the disparity in published data on the prognostic importance of hOCT1 mRNA and highlighting the importance of avoiding common SNP sites in primer design. These data demonstrate that the common M420del SNP can modulate the outcome of imatinib treatment.

Effects of CYP4F2 genetic polymorphisms and haplotypes on clinical outcomes in patients initiated on warfarin therapy.

BACKGROUND: A variant in the CYP4F2 gene, rs2108622, has been recently shown to determine stable warfarin dose requirements. CYP4F2 has also been shown recently to metabolize vitamin K. METHODS: Three hundred and eleven patients were recruited prospectively from two UK hospitals and followed-up for 6 months. Fine mapping of the whole CYP4F2 region was performed to try and define the haplotype structure of CYP4F2. Genotyping was performed on the Sequenom platform. Univariate and multiple regression analyses were undertaken to assess the effect of CYP4F2 on predefined clinical outcomes of warfarin response. RESULTS: Fifty-nine single nucleotide polymorphisms in the CYP4F2 gene were analyzed. There was a high degree of linkage disequilibrium in the gene with two haplotype blocks. No association was found with warfarin stable dose and rs2108622 in our prospective cohort of patients even after adjustments to reduce patient heterogeneity. Interestingly, a single nucleotide polymorphism (rs2189784), which is in strong linkage disequilibrium with rs2108622, showed an association with time-to-therapeutic international normalized ratio which remained significant after the correction for multiple testing (Pc = 0.03). No association was shown with the haplotypes after false discovery rate correction. CONCLUSION: Although we were unable to demonstrate an association between rs2108622 and stable warfarin dose, our finding of an association between rs2189784 and time-to-therapeutic international normalized ratio is consistent with the recent finding that CYP4F2 plays a role in vitamin K metabolism. However, the effect of CYP4F2 is relatively small in all studies undertaken so far, and thus seems unlikely to be of clinical relevance.

Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study.

BACKGROUND: In this prospective cohort study, we have undertaken a comprehensive evaluation of clinical parameters along with variation in 29 genes (including CYP2C9 and VKORC1) to identify factors determining interindividual variability in warfarin response. METHODS: Consecutive patients (n=311) were followed up prospectively for 26 weeks. Several outcomes chosen to capture both warfarin efficacy and toxicity were assessed. Univariate and multiple regression analyses were undertaken to assess the combined effect of clinical and genetic factors. RESULTS: CYP2C9 was the most important gene determining initial anticoagulant control, whereas VKORC1 was more important for stable anticoagulation. Novel associations with some clinical outcomes were found with single nucleotide polymorphisms in the cytochrome 450 genes CYP2C18 and CYP2C19, which were independent of the associations observed with CYP2C9 and in genes encoding CYP3A5, protein S and clotting factor V, although the variability explained by these genes was small. On the basis of the results of microcosting, adverse events were shown to be a significant predictor of total cost. CONCLUSION: Accurate prediction of warfarin dose requirement needs to take into account multiple genetic and environmental factors, the contributions of which vary in the induction and maintenance phases of treatment.