Pharmacogenetic studies relevant to pediatric oncology
| Study | Population | Gene and selected variants | Important findings | References |
|---|---|---|---|---|
| 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 XIIIB | TPMT*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 FOLFIRI | UGT1A1*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 cisplatin | TPMT: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 doses | SLC28A3: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 lymphoma | GSTP1: 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) | IL15 | • IL15 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. |