Histone Mark Profiling in Pediatric Astrocytomas Reveals Prognostic Significance of H3K9 Trimethylation and Histone Methyltransferase SUV39H1

171 Background: Along with genetic events, tumor associated epigenetic alterations including DNA methylation and post-translational histone modifications are important determinants in the initiation and progression of hepatocellular cancer (HCC) and represent promising biomarkers and therapeutic targets. Locus-specific trimethylation of histone H3 lysine 4 (H3K4me) is a well-known modification linked to the enhanced transcriptional expression of many genes activated in HCC. However its expression and association with prognosis of HCC patients remain unclear. Our aim was to assess the cellular expression pattern of H3K4me3 in HCC and its association with clinicopathologic variables and outcome. Methods: Expression of H3K4me3 and the histone methyltransferase SMYD3 was studied by western blotting and immunohistochemistry in human HCC cell lines and tumor tissue micmicroarray, which is from a well–characterized series of HCC patients(n=168). Tissue staining were assessed using blinded semiquantitative scoring. The optimal cut-point of H3K4me3 expression for prognosis was determined by the X-tile program. The prognostic significance was evaluated using Kaplan-Meier survival estimates and log-rank tests. Tumor tissue micmicroarray from another independent HCC patients cohort(n=147) was used for validation studies. Results: Expression of H3K4me3 and the histone methyltransferase SMYD3 were enhanced in HCC cell lines.In clinical tumor specimens, enhanced expression of H3K4me3 was correlated with reduced overall survival (P < 0.0001), especially in early-stage HCC patients(TNM I/II).Furthermore,both univariate and multivariate analysis revealed that H3K4me3 level was a significant and independent predictor of poor survival (hazard ratio,3.592; 95% CI, 2.302-5.605). In addition, H3K4m3 expression was positively correlated with SMYD3 expression in both testing and validation cohorts (P<0.0001). Conclusions: H3K4me3 level defines previously unrecognized subsets of HCC patients with distinct epigenetic phenotype and clinical outcome, thus can be a novel predictor for poor prognosis of HCC patients, especially within TNM I/IIstage.

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Ultrastructural features of prognostic significance in human oral cancer

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100123490 ◽

1992 ◽

Vol 50 (1) ◽

pp. 618-619

Author(s):

Karvita B. Ahluwalia ◽

Nidhi Sharma

Keyword(s):

Oral Cancer ◽

Squamous Cell ◽

Common Knowledge ◽

Prognostic Significance ◽

Growth Control ◽

Terminal Differentiation ◽

Squamous Cell Carcinomas ◽

Effective Therapy ◽

Invasive Potential ◽

Biological Behaviour

It is common knowledge that apparently similar tumors often show different responses to therapy. This experience has generated the idea that histologically similar tumors could have biologically distinct behaviour. The development of effective therapy therefore, has the explicit challenge of understanding biological behaviour of a tumor. The question is which parameters in a tumor could relate to its biological behaviour ? It is now recognised that the development of malignancy requires an alteration in the program of terminal differentiation in addition to aberrant growth control. In this study therefore, ultrastructural markers that relate to defective terminal differentiation and possibly invasive potential of cells have been identified in human oral leukoplakias, erythroleukoplakias and squamous cell carcinomas of the tongue.

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