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), γ-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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Acknowledgements
We thank of Y. Chu, N. Lenchik, P. Baker, N. Duran, E. Melton, P. McGill and M. Chung for technical support; C. Cheng for carrying out statistical analyses; S.R. Tate for carrying out microsatellite analyses; and N. Kornegay and M. Caldwell for their contributions in establishing our research databases and in preparing the manuscript. This work was supported in part by grants from the US National Institutes of Health (to W.E.E., M.V.R. and C.-H.P.; to M.V.R. and C.-H.P.; and to M.V.R. and W.E.E.), by the US National Institutes of Health Pharmacogenetics Research Network, by a Cancer Center Support Grant, by an FM Kirby Clinical Research Professorship from the American Cancer Society (to C.-H.P.) and by the American Lebanese Syrian Associated Charities.
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Supplementary information
Supplementary Fig. 1
Erythrocyte TPMT phenotype determined by radiochemical assay or by MMPN/TGN ratio. (PDF 79 kb)
Supplementary Fig. 2
Electropherograms of microsatellite analysis using fluorescently labeled markers. (PDF 73 kb)
Supplementary Fig. 3
Validation of quantitative allele specific real-time PCR for genotyping. (PDF 186 kb)
Supplementary Fig. 4
Concordance between genomic allele ratio and mRNA allelic expression ratio in individuals with heterozygous GGH 452C→T or TPMT*1/*3A genotypes. (PDF 146 kb)
Supplementary Table 1
Patient characteristics. (PDF 47 kb)
Supplementary Table 2
Quantitative ratio in reconstitution experiment. (PDF 66 kb)
Supplementary Table 3
Primer and probe sequence. (PDF 67 kb)
Supplementary Note
TPMT phenotype analysis, microsatellite analysis and allele-specific quantitation analysis. (PDF 86 kb)
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Cheng, Q., Yang, W., Raimondi, S. et al. Karyotypic abnormalities create discordance of germline genotype and cancer cell phenotypes. Nat Genet 37, 878–882 (2005). https://doi.org/10.1038/ng1612
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DOI: https://doi.org/10.1038/ng1612
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