Germline genetic variation and treatment response on CCG-1891.

TitleGermline genetic variation and treatment response on CCG-1891.
Publication TypeJournal Article
Year of Publication2012
AuthorsSepe DM, McWilliams T, Chen J, Kershenbaum A, Zhao H, La M, Devidas M, Lange B, Rebbeck TR, Aplenc R
JournalPediatr Blood Cancer
Volume58
Issue5
Pagination695-700
Date Published2012 May
ISSN1545-5017
KeywordsChild, Preschool, Female, Genetic Variation, Glutathione S-Transferase pi, Humans, Male, Methylenetetrahydrofolate Reductase (NADPH2), Methyltransferases, Polymorphism, Genetic, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Randomized Controlled Trials as Topic
Abstract

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.

DOI10.1002/pbc.23192
Alternate JournalPediatr Blood Cancer
PubMed ID21618417
PubMed Central IDPMC3165089
Grant ListR01 CA108862 / CA / NCI NIH HHS / United States
R01 CA108862 / CA / NCI NIH HHS / United States
R01 CA108862-01A1 / CA / NCI NIH HHS / United States
UL1 TR000064 / TR / NCATS NIH HHS / United States