Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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), 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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cytogenetic characteristics of ALL cells.
Figure 2: Chromosome number influences TPMT or GGH activity in B-lineage leukemia cells among individuals with heterozygous germline genotypes.
Figure 3: Quantitative allele-specific analysis of individuals with a heterozygous germline polymorphism and trisomy with respect to the corresponding chromosome in their leukemia cells.
Figure 4: GGH phenotype, GGH 452C → T genotypes and MTXPG accumulation.
Figure 5: Relation between TPMT phenotype and TPMT *1/*3A genotypes.
Figure 6: Relation between phenotype and the number of chromosomes with a wild-type allele.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Evans, W.E. & Relling, M.V. Moving towards individualized medicine with pharmacogenomics. Nature 429, 464–468 (2004).

    Article  CAS  Google Scholar 

  2. Evans, W.E. & McLeod, H.L. Pharmacogenomics–drug disposition, drug targets, and side effects. N. Engl. J. Med. 348, 538–549 (2003).

    Article  CAS  Google Scholar 

  3. Rajagopalan, H. & Lengauer, C. Aneuploidy and cancer. Nature 432, 338–341 (2004).

    Article  CAS  Google Scholar 

  4. Draviam, V.M., Xie, S. & Sorger, P.K. Chromosome segregation and genomic stability. Curr. Opin. Genet. Dev. 14, 120–125 (2004).

    Article  CAS  Google Scholar 

  5. Pui, C.H., Relling, M.V. & Downing, J.R. Acute lymphoblastic leukemia. N. Engl. J. Med. 350, 1535–1548 (2004).

    Article  CAS  Google Scholar 

  6. Pui, C.H. & Evans, W.E. Acute lymphoblastic leukemia. N. Engl. J. Med. 339, 605–615 (1998).

    Article  CAS  Google Scholar 

  7. Masson, E. et al. Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. A rationale for high-dose methotrexate. J. Clin. Invest. 97, 73–80 (1996).

    Article  CAS  Google Scholar 

  8. Lilleyman, J.S. & Lennard, L. Mercaptopurine metabolism and risk of relapse in childhood lymphoblastic leukaemia. Lancet 343, 1188–1190 (1994).

    Article  CAS  Google Scholar 

  9. Krynetski, E.Y., Krynetskaia, N.F., Yanishevski, Y. & Evans, W.E. Methylation of mercaptopurine, thioguanine, and their nucleotide metabolites by heterologously expressed human thiopurine S-methyltransferase. Mol. Pharmacol. 47, 1141–1147 (1995).

    CAS  PubMed  Google Scholar 

  10. Panetta, J.C., Wall, A., Pui, C.H., Relling, M.V. & Evans, W.E. Methotrexate intracellular disposition in acute lymphoblastic leukemia: a mathematical model of gamma-glutamyl hydrolase activity. Clin. Cancer Res. 8, 2423–2429 (2002).

    CAS  PubMed  Google Scholar 

  11. Belkov, V.M. et al. Reduced folate carrier expression in acute lymphoblastic leukemia: a mechanism for ploidy but not lineage differences in methotrexate accumulation. Blood 93, 1643–1650 (1999).

    CAS  PubMed  Google Scholar 

  12. Tai, H.L. et al. Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am. J. Hum. Genet. 58, 694–702 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Cheng, Q. et al. A substrate specific functional polymorphism of human gamma-glutamyl hydrolase alters catalytic activity and methotrexate polyglutamate accumulation in acute lymphoblastic leukaemia cells. Pharmacogenetics 14, 557–567 (2004).

    Article  CAS  Google Scholar 

  14. Chango, A. et al. A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol. Genet. Metab. 70, 310–315 (2000).

    Article  CAS  Google Scholar 

  15. Paulsson, K. et al. Formation of trisomies and their parental origin in hyperdiploid childhood acute lymphoblastic leukemia. Blood 102, 3010–3015 (2003).

    Article  CAS  Google Scholar 

  16. Synold, T.W. et al. Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. J Clin Invest 94, 1996–2001 (1994).

    Article  CAS  Google Scholar 

  17. Hanahan, D. & Weinberg, R.A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  Google Scholar 

  18. Albertson, D.G., Collins, C., McCormick, F. & Gray, J.W. Chromosome aberrations in solid tumors. Nat. Genet. 34, 369–376 (2003).

    Article  CAS  Google Scholar 

  19. Baak, J.P. et al. Genomics and proteomics in cancer. Eur. J. Cancer 39, 1199–1215 (2003).

    Article  CAS  Google Scholar 

  20. Bardi, G., Fenger, C., Johansson, B., Mitelman, F. & Heim, S. Tumor karyotype predicts clinical outcome in colorectal cancer patients. J. Clin. Oncol. 22, 2623–2634 (2004).

    Article  Google Scholar 

  21. Mayr, D. et al. Characteristic pattern of genetic aberrations in ovarian granulosa cell tumors. Mod. Pathol. 15, 951–957 (2002).

    Article  CAS  Google Scholar 

  22. Verdorfer, I. et al. Combined study of prostatic carcinoma by classical cytogenetic analysis and comparative genomic hybridization. Int. J. Oncol. 19, 1263–1270 (2001).

    CAS  PubMed  Google Scholar 

  23. Gollin, S.M. Chromosomal instability. Curr. Opin. Oncol. 16, 25–31 (2004).

    Article  Google Scholar 

  24. Masuda, A. & Takahashi, T. Chromosome instability in human lung cancers: possible underlying mechanisms and potential consequences in the pathogenesis. Oncogene 21, 6884–6897 (2002).

    Article  CAS  Google Scholar 

  25. Rivera, G.K. et al. Bone marrow recurrence after initial intensive treatment for childhood acute lymphoblastic leukemia. Cancer 103, 368–376 (2005).

    Article  Google Scholar 

  26. FitzPatrick, D.R. et al. Transcriptome analysis of human autosomal trisomy. Hum. Mol. Genet. 11, 3249–3256 (2002).

    Article  CAS  Google Scholar 

  27. Pui, C.H. et al. Rationale and design of Total Therapy Study XV for newly diagnosed childhood acute lymphoblastic leukemia. Ann. Hematol. 83 Suppl. 1, S124–S126 (2004).

    PubMed  Google Scholar 

  28. Mitelman, F. An International System for Human Cytogenetic Nomenclature (Karger, Basel, 1995).

    Google Scholar 

  29. Dervieux, T. et al. HPLC determination of thiopurine nucleosides and nucleotides in vivo in lymphoblasts following mercaptopurine therapy. Clin. Chem. 48, 61–68 (2002).

    CAS  PubMed  Google Scholar 

  30. Yates, C.R. et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann. Intern. Med. 126, 608–614 (1997).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to William E Evans.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1612

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing