Nature Genetics
37, 878 - 882 (2005)
Published online: 24 July 2005; | doi:10.1038/ng1612
Karyotypic abnormalities create discordance of germline genotype and cancer cell phenotypesQing Cheng1, WenJian Yang1, Susana C Raimondi2, Ching-Hon Pui3, Mary V Relling1
& William E Evans11
Hematological Malignancies Program, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105, USA. 2
Department of Pathology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105, USA. 3
Department of Hematology-Oncology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105, USA.
Correspondence should be addressed to William E Evans william.evans@stjude.org 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),  -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.
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