Global histone modifications predict prognosis of resected non-small cell lung cancer patients
7662 Background: Epigenetic modifications, such as methylation and/or acetylation of histones, may contribute to the development and progression of cancer. We investigated whether histone modifications influence prognosis of non-small cell lung cancer (NSCLC). Methods: We used immunohistochemistry to assess histone 3 lysine 4 dimethylation (H3K4diMe), and acetylation of histone 2A lysine 5 (H2AK5Ac), histone 2B lysine 12 (H2BK12Ac), histone 3 lysine 9 (H3K9Ac), and histone 4 lysine 8 (H4K8Ac), in resected tumor samples of 138 NSCLC patients. In addition, the genotype of a tandem repeat polymorphism in the histone 3 methyltransferase SMYD3 gene was determined using PCR and capillary electrophoresis. Data were analyzed using a recursive partitioning analysis (RPA). Results: The overall median expression of H3K4diMe, H2AK5Ac, H2BK12Ac, H3K9Ac, and H4K8Ac were 75, 10, 0, 25, and 80%, respectively. The RPA classified the patients into seven distinct prognostic groups based on TNM stage (first node), histology (second node) and histone modifications (third node). H3K4diMe (< or =85% tumor cells), H3K9Ac (< or =68% tumor cells) and H2AKAc (< or =5% tumor cells) were retained by RPA. The SMYD3 genotype was not retained by RPA. The seven groups were associated with significantly different disease- free (p<0.0001) and overall survival (p<0.0001). Interestingly, the four groups determined by stage I patients (below the first node) displayed dramatic differences in survival (median from 10 months in adenocarcinoma, H3K9Ac=68%, to 147 months in non-adenocarcinoma, H3K4diMe=85%). Conclusions: The prognostic influence of global histone modifications is greater in early stage NSCLC and it may help in the selection of early stage NSCLC patients for adjuvant treatment and provides a rationale for the use of combination of standard chemotherapy with drugs interacting with histone modifications such as histone deacetylases (HDAC) inhibitors. No significant financial relationships to disclose.