Table 1.

Pharmacogenetic studies relevant to pediatric oncology

StudyPopulationGene and selected variantsImportant findingsReferences
Relling et al. (2006)Pharmacogenetic dosing of 6-MP in 246 patients (231 homozygous WT and 15 heterozygous variant) with ALL treated prospectively on St. Jude Protocol Total XIIIBTPMT*2• Variant alleles have decreased ability to inactivate TGNs, leading to increased adverse events. Reduced dosing strategy for heterozygous variant patients showed no difference in risk of relapse or acute toxicity.(25, 26)
Stocco et al. (2009)TPMT*3A• Reduced dosing strategy for heterozygous variant patients showed no difference in risk of relapse or acute toxicity.
TPMT*3B
TPMT*3C
Marcuello et al. (2011)Ninety-four Spanish adults with metastatic colorectal cancer being treated prospectively with FOLFIRIUGT1A1*28• A 7-TA repeat in the promoter region leads to decreased enzyme activity.(33)
• Genotype-directed dosing strategies allowed for dose escalations in WT and heterozygous patients.
Ross et al. (2009)DME variant microarray study of 166 children (54 in test cohort, 112 in validation) with various malignancies treated with a median of 360 mg/m2 cumulative cisplatinTPMT:rs12201199 A/T• Variant alleles in TPMT and COMT identified in this analysis in linkage disequilibrium with nonfunctional alleles.(38)
COMT:rs9332377 A/G• Unique carriers of either variant allele had a 12-fold increase in ototoxicity.
Visscher et al. (2011)DME variant microarray study of 440 children (156 in test cohort, 284 in 2 validation cohorts) with various malignancies treated with various cumulative anthracycline dosesSLC28A3:rs7853758 C/T• Patients with variant alleles were protected from anthracycline cardiotoxicity (OR 0.31; 95% CI, 0.16–0.6).(46)
• Combination with 8 additional variants able to construct a model predictive for development of cardiotoxicity.
Chen et al. (2010)GWAS of asparaginase hypersensitivity in 485 children with ALL (322 in discovery and 163 in validation cohorts)GRIA1• Excess of associations at 5q33 in intronic regions of GRIA1 locus.(10)
• Unclear significance of GRIA1 in immune function and hypersensitivity.
Stanulla et al. (2005)Sixty-eight children (34 cases, 34 controls) with ALL and 97 patients with Hodgkin lymphomaGSTP1: rs1695 A/G• Missense variant leading to decreased enzyme activity.• Homozygous variants with ALL at decreased risk of CNS relapse(6, 7)
Hohaus et al. (2005)• In patients with Hodgkin lymphoma, a variant allele was found to predict OS in a dose-dependent manner.
Yang et al. (2009)GWAS of treatment response in 487 children with ALL (318 in test cohort, 169 in validation)IL15IL15 is a proliferation-enhancing cytokine that was previously linked to glucocorticoid resistance.(8)
Yang et al. (2010)GWAS of relapse in 2,534 children with ALL, including 405 children of Native American ancestry.PDE4B:rs6683977 C/G• Top associated SNP with relapse risk in PDE4B.(9)
• Leukemic blasts with higher PDE4B expression were more resistant to prednisolone.
• SNP was associated with Native American ancestry and may partially explain ethnic disparities in relapse risk.