Germline Genetic Variation and Treatment Response on CCG-1891

Recent studies have suggested that polymorphisms in genes that encode enzymes involved in drug detoxification and metabolism may influence disease outcome in pediatric patients with acute lymphoblastic leukemia (ALL). We sought to extend current knowledge by using standard and novel statistical methodology to examine how frequency of polymorphism variants of certain drug metabolizing genes and gene pairs relate to relapse risk, toxicity, and drug dose delivery in standard risk ALL.

We genotyped and abstracted chemotherapy drug dose data from treatment roadmaps on 557 patients on the Children's Cancer Group ALL study, CCG-1891. These data were analyzed with outcome data obtained from CCG. Fourteen common polymorphisms in genes involved in folate metabolism and/or phase I and II drug detoxification were evaluated individually by univariate analysis and clique-finding methodology was employed for detection of significant gene-gene interactions. Additionally, positive predictive value was calculated for those polymorphisms found to be statistically significant on univariate analysis.

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. However, the positive predictive value of these genotypes was not statistically significant. 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.

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.

No relevant conflicts of interest to declare.