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Global histone modification patterns predict risk of prostate cancer recurrence

Abstract

Aberrations in post-translational modifications of histones have been shown to occur in cancer cells but only at individual promoters1; they have not been related to clinical outcome. Other than being targeted to promoters, modifications of histones, such as acetylation and methylation of lysine and arginine residues, also occur over large regions of chromatin including coding regions and non-promoter sequences, which are referred to as global histone modifications2. Here we show that changes in global levels of individual histone modifications are also associated with cancer and that these changes are predictive of clinical outcome. Through immunohistochemical staining of primary prostatectomy tissue samples, we determined the percentage of cells that stained for the histone acetylation and dimethylation of five residues in histones H3 and H4. Grouping of samples with similar patterns of modifications identified two disease subtypes with distinct risks of tumour recurrence in patients with low-grade prostate cancer. These histone modification patterns were predictors of outcome independently of tumour stage, preoperative prostate-specific antigen levels, and capsule invasion. Thus, widespread changes in specific histone modifications indicate previously undescribed molecular heterogeneity in prostate cancer and might underlie the broad range of clinical behaviour in cancer patients.

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Figure 1: Global levels of individual histone modifications are determined by immunohistochemistry.
Figure 2: Grouping of patients with similar histone modification patterns.
Figure 3: Grouping of patients with low-grade tumours with similar histone modification patterns.
Figure 4: Histone modification patterns predict tumour recurrence.

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References

  1. Jacobson, S. & Pillus, L. Modifying chromatin and concepts of cancer. Curr. Opin. Genet. Dev. 9, 175–184 (1999)

    Article  CAS  PubMed  Google Scholar 

  2. Vogelauer, M., Wu, J., Suka, N. & Grunstein, M. Global histone acetylation and deacetylation in yeast. Nature 408, 495–498 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  3. Jemal, A. et al. Cancer statistics, 2003. CA Cancer J. Clinicians 53, 5–26 (2003)

    Article  Google Scholar 

  4. Gleason, D. F. Classification of prostatic carcinomas. Cancer Chemother. Rep. 50, 125–128 (1966)

    CAS  PubMed  Google Scholar 

  5. Bunting, P. S. Screening for prostate cancer with prostate-specific antigen: beware the biases. Clin. Chim. Acta 315, 71–97 (2002)

    Article  CAS  PubMed  Google Scholar 

  6. Han, M., Partin, A. W., Piantadosi, S., Epstein, J. I. & Walsh, P. C. Era specific biochemical recurrence-free survival following radical prostatectomy for clinically localized prostate cancer. J. Urol. 166, 416–419 (2001)

    Article  CAS  PubMed  Google Scholar 

  7. Farkas, A., Schneider, D., Perrotti, M., Cummings, K. B. & Ward, W. S. National trends in the epidemiology of prostate cancer, 1973 to 1994: evidence for the effectiveness of prostate-specific antigen screening. Urology 52, 444–448 (1998)

    Article  CAS  PubMed  Google Scholar 

  8. Giles, R. H., Peters, D. J. & Breuning, M. H. Conjunction dysfunction: CBP/p300 in human disease. Trends Genet. 14, 178–183 (1998)

    Article  CAS  PubMed  Google Scholar 

  9. Gayther, S. A. et al. Mutations truncating the EP300 acetylase in human cancers. Nature Genet. 24, 300–303 (2000)

    Article  CAS  PubMed  Google Scholar 

  10. Muraoka, M. et al. p300 gene alterations in colorectal and gastric carcinomas. Oncogene 12, 1565–1569 (1996)

    CAS  PubMed  Google Scholar 

  11. Debes, J. D. et al. p300 in prostate cancer proliferation and progression. Cancer Res. 63, 7638–7640 (2003)

    CAS  PubMed  Google Scholar 

  12. Reid, J. L., Iyer, V. R., Brown, P. O. & Struhl, K. Coordinate regulation of yeast ribosomal protein genes is associated with targeted recruitment of Esa1 histone acetylase. Mol. Cell 6, 1297–1307 (2000)

    Article  CAS  PubMed  Google Scholar 

  13. Krebs, J. E., Fry, C. J., Samuels, M. L. & Peterson, C. L. Global role for chromatin remodeling enzymes in mitotic gene expression. Cell 102, 587–598 (2000)

    Article  CAS  PubMed  Google Scholar 

  14. Peterson, C. L. & Laniel, M. A. Histones and histone modifications. Curr. Biol. 14, R546–R551 (2004)

    Article  CAS  PubMed  Google Scholar 

  15. Suka, N., Suka, Y., Carmen, A. A., Wu, J. & Grunstein, M. Highly specific antibodies determine histone acetylation site usage in yeast heterochromatin and euchromatin. Mol. Cell 8, 473–479 (2001)

    Article  CAS  PubMed  Google Scholar 

  16. Kononen, J. et al. Tissue microarrays for high-throughput molecular profiling of tumour specimens. Nature Med. 4, 844–847 (1998)

    Article  CAS  PubMed  Google Scholar 

  17. Kurdistani, S. K., Tavazoie, S. & Grunstein, M. Mapping global histone acetylation patterns to gene expression. Cell 117, 721–733 (2004)

    Article  CAS  PubMed  Google Scholar 

  18. Rezai-Zadeh, N. et al. Targeted recruitment of a histone H4-specific methyltransferase by the transcription factor YY1. Genes Dev. 17, 1019–1029 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Breiman, L. Classification and Regression Trees (Wadsworth International, Belmont, California, 1984)

    MATH  Google Scholar 

  20. Breiman, L. Random forests. Mach. Learn. 45, 5–32 (2001)

    Article  Google Scholar 

  21. Shi, T., Seligson, D., Belldegrun, A. S., Palotie, A. & Horvath, S. Tumor classification by tissue microarray profiling: random forest clustering applied to renal cell carcinoma. Mod. Pathol. 18, 547–557 (2005)

    Article  CAS  PubMed  Google Scholar 

  22. Kaplan, E. & Meier, P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53, 457–481 (1958)

    Article  MathSciNet  Google Scholar 

  23. Cleveland, W. S. Visualizing Data (Hobart Press, Murray Hill, New Jersey, 1993)

    Google Scholar 

  24. Fraga, M. F. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature Genet. 37, 391–400 (2005)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Vogelauer for suggestions on the manuscript, and V. Minin for help with the statistical analyses. T.S. was a doctoral trainee supported by the UCLA Integrative Graduate Education and Research Traineeship (IGERT) Bioinformatics Program funded by the NSF Division of Graduate Education (DGE). This work was funded partly by a National Cancer Institute (NCI)] grant through the Jonsson Comprehensive Cancer Center to D.B.S. and a Howard Hughes Medical Institute Fellowship and a UCLA Specialized Program Of Research Excellence (SPORE) in Prostate Cancer Career Development grant to S.K.K.

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Correspondence to Siavash K. Kurdistani.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Table S1

Univariate Cox analysis of level of individual histone modifications and risk of tumour recurrence. (DOC 26 kb)

Supplementary Table S2

Relationship of histone modification groups with clinicopathologic parameters in low grade (Gleason score=2-6) prostate adenocarcinomas (n=104). (DOC 79 kb)

Supplementary Table S3

Relationship of histone modification groups with clinicopathologic parameters in low grade (Gleason score=5-6) prostate adenocarcinomas from the Michigan validation TMA (n=39). (DOC 80 kb)

Supplementary Figure S1

Histone modification antibodies are specific in immunohistochemistry. (PDF 916 kb)

Supplementary Figure S2

A ′simple rule′ involving H3 K4diMe and H3 K18Ac estimates the grouping of patients based on Random Forests clustering of all five histone modifications. (PDF 51 kb)

Supplementary Methods

Detailed protocols and procedures used in this study. (DOC 61 kb)

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Seligson, D., Horvath, S., Shi, T. et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435, 1262–1266 (2005). https://doi.org/10.1038/nature03672

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