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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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.
Univariate Cox analysis of level of individual histone modifications and risk of tumour recurrence. (DOC 26 kb)
Relationship of histone modification groups with clinicopathologic parameters in low grade (Gleason score=2-6) prostate adenocarcinomas (n=104). (DOC 79 kb)
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)
Histone modification antibodies are specific in immunohistochemistry. (PDF 916 kb)
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)
Detailed protocols and procedures used in this study. (DOC 61 kb)
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