title: Global gene expression as a function of germline genetic variation.
abstract: Common, functional, germline genetic polymorphisms have been associated with clinical cancer outcomes. Little attention has been paid to the potential phenotypic consequences of germline genetic variation on downstream genes. We determined the germline status of 16 well-characterized functional polymorphisms in 126 children with newly diagnosed acute lymphoblastic leukemia (ALL). We assessed whether global gene expression profiles of diagnostic ALL blasts from the same patients differed by these germline polymorphic genotypes. Gene expression values were adjusted for ALL-subtype-specific patterns. Of the 16 loci, only the UGT1A1 promoter repeat polymorphism [A(TA)nTAA] (UGT1A1*28) and GSTM1 deletion were significant predictors of global gene expression in a supervised approach, which divided patients based on their germline genotypes [UGT1A1: 124 probe sets, false discovery rate (FDR)=13%, P< or =0.0031; GSTM1: 112 probe sets, FDR=42.5%, P< or =0.0084]. Genes whose expression distinguished the UGT1A1 (TA) 7/7 genotype from the other UGT1A1 genotypes included HDAC1, RELA and SLC2A1; those that distinguished the GSTM1 null genotype from non-null genotype included NBS1 and PRKR. In an unsupervised approach, the gene expression profiles using the entire array delineated two major clusters of patients. The only germline genotype frequency that differed between the two clusters was UGT1A1 (P=0.002; Fisher's exact test). Although their expression is limited to specific tissues, both GSTM1 and UGT1A1 are involved in the conjugation (and thus transport, excretion and lipophilicity) of a broad range of endobiotics and xenobiotics, which could plausibly have consequences for gene expression in different tissues.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: French
authors.forename: Mark R
authors.initials: MR
authors.lastname: Wilkinson
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.forename: Luc
authors.initials: L
authors.lastname: de Chaisemartin
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D002648:Child; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D014644:Genetic Variation; D005838:Genotype; D018095:Germ-Line Mutation; D014453:Glucuronosyltransferase / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017384:Sequence Deletion; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D000099148:UGT1A1 Enzyme