Genetic clonal diversity predicts progression to esophageal adenocarcinoma

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Abstract

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.

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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.

References

  1. 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).

  2. 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).

  3. 3

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

  4. 4

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

  5. 5

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

  6. 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).

  7. 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).

  8. 8

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

  9. 9

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

  10. 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).

  11. 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).

  12. 12

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

  13. 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).

  14. 14

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

  15. 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).

  16. 16

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

  17. 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).

  18. 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).

  19. 19

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

  20. 20

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

  21. 21

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

  22. 22

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

  23. 23

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

  24. 24

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

  25. 25

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

  26. 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).

  27. 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).

  28. 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).

  29. 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).

  30. 30

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

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Acknowledgements

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.

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Correspondence to Carlo C Maley.

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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)

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