title: Karyotypic abnormalities create discordance of germline genotype and cancer cell phenotypes.
abstract: The nature of mendelian inheritance assumes that all tissues in which a phenotype of interest is expressed have a uniform diploid karyotype, which is often not the case in cancer cells. Owing to nonrandom gains of chromosomes, trisomies are present in many cases of leukemia and other malignances. We used polymorphisms in the genes encoding thiopurine S-methyltransferase (TPMT), gamma-glutamyl hydrolase (GGH) and the reduced folate carrier (SLC19A1) to assess the nature of chromosomal acquisition and its influence on genotype-phenotype concordance in cancer cells. TPMT and GGH activities in somatic cells were concordant with germline genotypes, whereas activities in leukemia cells were determined by chromosomal number and whether the acquired chromosomes contained a wild-type or variant allele. Leukemia cells that had acquired an additional chromosome containing a wild-type TPMT or GGH allele had significantly lower accumulation of thioguanine nucleotides or methotrexate polyglutamates, respectively. Among these genes, there was a comparable number of acquired chromosomes with wild-type and variant alleles. Therefore, chromosomal gain can alter the concordance of germline genotype and cancer cell phenotypes, indicating that allele-specific quantitative genotyping may be required to define cancer pharmacogenomics unequivocally.
authors.affiliation: Hematological Malignancies Program, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Cheng
authors.forename: WenJian
authors.initials: W
authors.lastname: Yang
authors.forename: Susana C
authors.initials: SC
authors.lastname: Raimondi
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
mesh_terms: D000293:Adolescent; D002051:Burkitt Lymphoma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005838:Genotype; D005854:Germ Cells; D006801:Humans; D007223:Infant; D007621:Karyotyping; D026901:Membrane Transport Proteins / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics; D018895:Microsatellite Repeats / Q000235:genetics; D010641:Phenotype; D058978:Reduced Folate Carrier Protein; D011623:gamma-Glutamyl Hydrolase / Q000235:genetics
chemical_list: D026901:Membrane Transport Proteins; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D011623:gamma-Glutamyl Hydrolase