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Germline genetic variation and treatment response on CCG‐1891
Author(s) -
Sepe Dana M.,
McWilliams Thomas,
Chen Jinbo,
Kershenbaum Aaron,
Zhao Huaqing,
La Mei,
Devidas Meenakshi,
Lange Beverly,
Rebbeck Timothy R.,
Aplenc Richard
Publication year - 2012
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.23192
Subject(s) - mtrr , gstp1 , medicine , methylenetetrahydrofolate reductase , genotype , cyp3a5 , pharmacogenetics , oncology , disease , gene , genetics , biology
Background Recent studies suggest that polymorphisms in genes encoding enzymes involved in drug detoxification and metabolism may influence disease outcome in pediatric acute lymphoblastic leukemia (ALL). We sought to extend current knowledge by using standard and novel statistical methodology to examine polymorphic variants of genes and relapse risk, toxicity, and drug dose delivery in standard risk ALL. Procedure We genotyped and abstracted chemotherapy drug dose data from treatment roadmaps on 557 patients on the Children's Cancer Group ALL study, CCG‐1891. Fourteen common polymorphisms in genes involved in folate metabolism and/or phase I and II drug detoxification were evaluated individually and clique‐finding methodology was employed for detection of significant gene–gene interactions. Results After controlling for known risk factors, polymorphisms in four genes: GSTP1*B (HR = 1.94, P = 0.047), MTHFR (HR = 1.61, P = 0.034), MTRR (HR = 1.95, P = 0.01), and TS (3R/4R, HR = 3.69, P = 0.007) were found to significantly increase relapse risk. One gene–gene pair, MTRR A/G and GSTM1 null genotype, significantly increased the risk of relapse after correction for multiple comparisons ( P = 0.012). Multiple polymorphisms were associated with various toxicities and there was no significant difference in dose of chemotherapy delivered by genotypes. Conclusions These data suggest that various polymorphisms play a role in relapse risk and toxicity during childhood ALL therapy and that genotype does not play a role in adjustment of drug dose administered. Additionally, gene–gene interactions may increase the risk of relapse in childhood ALL and the clique method may have utility in further exploring these interactions. childhood ALL therapy. Pediatr Blood Cancer 2012; 58: 695–700. © 2011 Wiley Periodicals, Inc.