title: Acquired variation outweighs inherited variation in whole genome analysis of methotrexate polyglutamate accumulation in leukemia.
abstract: Methotrexate polyglutamates (MTXPGs) determine in vivo efficacy in acute lymphoblastic leukemia (ALL). MTXPG accumulation differs by leukemic subtypes, but genomic determinants of MTXPG variation in ALL remain unclear. We analyzed 3 types of whole genome variation: leukemia cell gene expression and somatic copy number variation, and inherited single nucleotide polymorphism (SNP) genotypes and determined their association with MTXPGs in leukemia cells. Seven genes (FHOD3, IMPA2, ME2, RASSF4, SLC39A6, SMAD2, and SMAD4) displayed all 3 types of genomic variation associated with MTXPGs (P < .05 for gene expression, P < .01 for copy number variation and SNPs): 6 on chromosome 18 and 1 on chromosome 10. Increased chromosome 18 (P = .002) or 10 (P = .036) copy number was associated with MTXPGs even after adjusting for ALL subtype. The expression of the top 7 genes in leukemia cells accounted for more variation in MTXPGs (46%) than did the expression of the top 7 genes in normal HapMap cell lines (20%). The top 7 inherited SNPs in patients accounted for approximately the same degree of variation (17%) in MTXPGs as did the top 7 SNP genotypes in HapMap cell lines (20%). We conclude that acquired genetic variation in leukemia cells has a stronger influence on MTXPG accumulation than inherited genetic variation.
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: Wenjian
authors.initials: W
authors.lastname: Yang
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.forename: Susana C
authors.initials: SC
authors.lastname: Raimondi
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D000080865:Formins; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D007223:Infant; D008291:Malate Dehydrogenase / Q000235:genetics; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051899:Smad2 Protein / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D027682:Cation Transport Proteins; C485994:FHOD3 protein, human; D000080865:Formins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; C495500:RASSF4 protein, human; C418627:SLC39A6 protein, human; C497782:SMAD2 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051901:Smad4 Protein; D025521:Tumor Suppressor Proteins; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D008291:Malate Dehydrogenase; C495394:malic enzyme 2; human; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D008727:Methotrexate