Global Gene Expression in Leukemic Blasts as a Function of Germline Genetic Variation.

The possible impact of common, functional, germline polymorphisms on clinical outcome in patients with leukemia is under active investigation. However, little attention has been paid to the possible consequences of germline genetic variation on genome-wide phenotypic variation in human tissues. We determined the germline status of 16 well-characterized functional genetic polymorphisms (using normal leukocyte cell DNA) in unrelated children with newly diagnosed acute lymphoblastic leukemia (ALL). We assessed whether global gene expression (using oligonucleotide arrays that interrogated approximately 10,000 genes) of diagnostic ALL blasts from the same patients differed by germline polymorphic genotypes. Gene expression values were adjusted for ALL-subtype-specific patterns. In a supervised analysis that divided patients based on their germline genotypes, we identified two polymorphisms that were significant predictors of global gene expression: the UGT1A1 promoter repeat polymorphism [A(TA)nTAA] (181 probe sets, p=0.01, false discovery rate [FDR] = 35.6%) and the GSTM1 deletion (112 probe sets, p=0.008, FDR = 42.5%). Genes whose expression differed significantly in ALL cells from patients with and without the UGT1A1 (TA) 7/7 genotype included ATM and ABL1; genes whose expression differed significantly between patients with the GSTM1 null genotype and the non-null genotype included PCNA, PRIM1, CDC6 and SKP1A. In an unsupervised analysis, patients were separated into two clusters; only the UGT1A1 promoter repeat polymorphism differed in frequency between the two clusters (p=0.001, Fisher’s exact test). These findings illustrate that polymorphisms in genes whose direct products are restricted to other tissues (e.g. UGT1A1 is primarily expressed hepatically) may affect gene expression elsewhere (e.g. ALL blasts). Because UGT1A1 is involved in the conjugation (and thus the transport and excretion) of numerous endogenous steroids and hormones, it is plausible that genotypic variation in its activity could have consequences for gene expression in distant tissues, such as ALL blasts.