Skip to main content

Thank you for visiting 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.

Genetic clonal diversity predicts progression to esophageal adenocarcinoma


Neoplasms are thought to progress to cancer through genetic instability generating cellular diversity1,2 and clonal expansions driven by selection for mutations in cancer genes3,4. Despite advances in the study of molecular biology of cancer genes5, relatively little is known about evolutionary mechanisms that drive neoplastic progression. It is unknown, for example, which may be more predictive of future progression of a neoplasm: genetic homogenization of the neoplasm, possibly caused by a clonal expansion, or the accumulation of clonal diversity. Here, in a prospective study, we show that clonal diversity measures adapted from ecology and evolution can predict progression to adenocarcinoma in the premalignant condition known as Barrett's esophagus, even when controlling for established genetic risk factors, including lesions in TP53 (p53; ref. 6) and ploidy abnormalities7. Progression to cancer through accumulation of clonal diversity, on which natural selection acts, may be a fundamental principle of neoplasia with important clinical implications.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Clonal diversity in four Barrett's segments.
Figure 2: Primary flow cytometric and microsatellite LOH data from clones B, C, D and F in Individual 1 (Fig. 1).
Figure 3: Kaplan-Meier cancer incidence curves for clonal diversity measures.


  1. Gonzalez-Garcia, I., Sole, R.V. & Costa, J. Metapopulation dynamics and spatial heterogeneity in cancer. Proc. Natl. Acad. Sci. USA 99, 13085–13089 (2002).

    CAS  Article  Google Scholar 

  2. Rajagopalan, H., Nowak, M.A., Vogelstein, B. & Lengauer, C. The significance of unstable chromosomes in colorectal cancer. Nat. Rev. Cancer 3, 695–701 (2003).

    CAS  Article  Google Scholar 

  3. Nowell, P.C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).

    CAS  Article  Google Scholar 

  4. Sieber, O.M., Heininmann, K. & Tomlinson, I.P. Genomic instability - the engine of tumorigenesis? Nat. Rev. Cancer 3, 701–708 (2003).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  6. Reid, B.J. et al. Predictors of progression in Barrett's esophagus II: baseline 17p (p53) loss of heterozygosity identifies a patient subset at increased risk for neoplastic progression. Am. J. Gastroenterol. 96, 2839–2848 (2001).

    CAS  Article  Google Scholar 

  7. Rabinovitch, P.S., Longton, G., Blount, P.L., Levine, D.S. & Reid, B.J. Predictors of progression in Barrett's esophagus III: baseline flow cytometric variables. Am. J. Gastroenterol. 96, 3071–3083 (2001).

    CAS  Article  Google Scholar 

  8. Breivik, J. The evolutionary origin of genetic instability in cancer development. Semin. Cancer Biol. 15, 51–60 (2005).

    CAS  Article  Google Scholar 

  9. Tsao, J.L. et al. Genetic reconstruction of individual colorectal tumor histories. Proc. Natl. Acad. Sci. USA 97, 1236–1241 (2000).

    CAS  Article  Google Scholar 

  10. Maley, C.C. et al. Selectively advantageous mutations and hitchhikers in neoplasms: p16 lesions are selected in Barrett's esophagus. Cancer Res. 64, 3414–3427 (2004).

    CAS  Article  Google Scholar 

  11. Boland, C.R. et al. A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 58, 5248–5257 (1998).

    CAS  PubMed  Google Scholar 

  12. Barrett, M.T. et al. Evolution of neoplastic cell lineages in Barrett oesophagus. Nat. Genet. 22, 106–109 (1999).

    CAS  Article  Google Scholar 

  13. Wong, D.J. et al. p16 INK4a lesions are common, early abnormalities that undergo clonal expansion in Barrett's metaplastic epithelium. Cancer Res. 61, 8284–8289 (2001).

    CAS  PubMed  Google Scholar 

  14. Haggitt, R.C. Barrett's esophagus, dysplasia, and adenocarcinoma. Hum. Pathol. 25, 982–993 (1994).

    CAS  Article  Google Scholar 

  15. Rudolph, R.E. et al. The effect of segment length on the risk of neoplastic progression in patients with Barrett's esophagus. Ann. Intern. Med. 132, 612–620 (2000).

    CAS  Article  Google Scholar 

  16. Doak, S.H. et al. Chromosome 4 hyperploidy represents an early genetic aberration in premalignant Barrett's oesophagus. Gut 52, 623–628 (2003).

    CAS  Article  Google Scholar 

  17. Conio, M. et al. Long-term endoscopic surveillance of patients with Barrett's esophagus. Incidence of dysplasia and adenocarcinoma: a prospective study. Am. J. Gastroenterol. 98, 1931–1939 (2003).

    Article  Google Scholar 

  18. Macdonald, C.E., Wicks, A.C. & Playford, R.J. Final results from 10 year cohort of patients undergoing surveillance for Barrett's oesophagus: observational study. Br. Med. J. 321, 1252–1255 (2000).

    CAS  Article  Google Scholar 

  19. Shackney, S.E. & Shackney, T.V. Common patterns of genetic evolution in human solid tumors. Cytometry 29, 1–27 (1997).

    CAS  Article  Google Scholar 

  20. Rocco, J.W. & Sidransky, D. p16(MTS-1/CDKN2/INK4a) in cancer progression. Exp. Cell Res. 264, 42–55 (2001).

    CAS  Article  Google Scholar 

  21. Sherr, C.J. Tumor surveillance via the ARF-p53 pathway. Genes Dev. 12, 2984–2991 (1998).

    CAS  Article  Google Scholar 

  22. Sampliner, R.E. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett's esophagus. Am. J. Gastroenterol. 97, 1888–1895 (2002).

    Article  Google Scholar 

  23. Magurran, A.E. Measuring Biological Diversity (Blackwell, Malden, Massachusetts, 2004).

    Google Scholar 

  24. Clarke, K.R. & Warwick, R.M. A taxonomic distinctness index and its statistical properties. J. Appl. Ecol. 35, 523–531 (1998).

    Article  Google Scholar 

  25. Nei, M. Molecular Evolutionary Genetics (Columbia Univ. Press, New York, 1987).

    Google Scholar 

  26. Rabinovitch, P.S., Reid, B.J., Haggitt, R.C., Norwood, T.H. & Rubin, C.E. Progression to cancer in Barrett's esophagus is associated with genomic instability. Lab. Invest. 60, 65–71 (1989).

    CAS  PubMed  Google Scholar 

  27. Palanca-Wessels, M.C. et al. Extended lifespan of Barrett's esophagus epithelium transduced with the human telomerase catalytic subunit: a useful in vitro model. Carcinogenesis 24, 1183–1190 (2003).

    CAS  Article  Google Scholar 

  28. Maley, C.C. et al. The combination of genetic instability and clonal expansion predicts progression to esophageal adenocarcinoma. Cancer Res. 64, 7629–7633 (2004).

    CAS  Article  Google Scholar 

  29. Levine, D.S., Blount, P.L., Rudolph, R.E. & Reid, B.J. Safety of a systematic endoscopic biopsy protocol in patients with Barrett's esophagus. Am. J. Gastroenterol. 95, 1152–1157 (2000).

    CAS  Article  Google Scholar 

  30. O'Sullivan, J.N. et al. Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat. Genet. 32, 280–284 (2002).

    CAS  Article  Google Scholar 

Download references


We thank R. Klausner, S. Self, S. Moolgavkar and H. Tang for their helpful suggestions. This work was supported by grants from the US National Institutes of Health (P01 CA91955, K01 CA89267-02 and K07 CA89147-03) and from funds provided by the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Carlo C Maley.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

The relationship between number of samples from a Barrett's segment and diversity measures. (PDF 264 kb)

Supplementary Note (PDF 88 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Maley, C., Galipeau, P., Finley, J. et al. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat Genet 38, 468–473 (2006).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


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