title: Nuclear expression of histone deacetylases and their histone modifications predicts clinical outcome in colorectal cancer.
abstract: OBJECTIVE
  Epigenetic changes are of crucial importance in cancer development and are potentially reversible; they are therefore targets of interest for anti-cancer therapy. The aim of this study was to investigate the clinical prognostic value of the histone deacetylases SIRT1, HDAC1 and HDAC2 and the histone modifications H4K16Ac and H3K56Ac in colorectal cancer.
  
  
  RESULTS
  The epigenetic markers were immunohistochemically stained on tissue microarrays containing colorectal tumours (n = 254) and normal colorectal tissues (n = 50). Nuclear expression was assessed on the semi-automated Ariol system. Multivariate trend survival analyses of the combined markers showed better patient survival and less tumour recurrence when more markers showed high nuclear expression. For the combination of the histone deacetylases and H3K56Ac, the hazard ratio (HR) for overall survival (OS) was 0.82 [95% confidence interval (CI) 0.72-0.94; P = 0.005] and the HR for distant recurrence-free survival (DRFS) was 0.77 (95% CI 0.64-0.92; P = 0.003) per additional marker showing high expression. Similarly, for the combination of histone deactylases and H4K16Ac, HRs of 0.86 (95% CI 0.76-0.97; P = 0.01) for OS and 0.79 (95% CI 0.68-0.93; P = 0.006) for DRFS were observed per additional marker showing high expression.
  
  
  CONCLUSIONS
  The studied epigenetic markers showed clinical prognostic value in colorectal cancer, both as individual markers and when combined into multimarker analyses. These results indicate that epigenetic mechanisms play an important role in colorectal carcinogenesis.
authors.affiliation: Department of Surgical Oncology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Anne
authors.initials: A
authors.lastname: Benard
authors.forename: Inès J
authors.initials: IJ
authors.lastname: Goossens-Beumer
authors.forename: Anneke Q
authors.initials: AQ
authors.lastname: van Hoesel
authors.forename: Hamed
authors.initials: H
authors.lastname: Horati
authors.forename: Wouter
authors.initials: W
authors.lastname: de Graaf
authors.forename: Hein
authors.initials: H
authors.lastname: Putter
authors.forename: Eliane C M
authors.initials: EC
authors.lastname: Zeestraten
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: Liefers
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: Peter J K
authors.initials: PJ
authors.lastname: Kuppen
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000401:mortality / Q000473:pathology*; D044127:Epigenesis, Genetic; D005260:Female; D006655:Histone Deacetylases / Q000032:analysis / Q000096:biosynthesis*; D006657:Histones / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones; D006655:Histone Deacetylases
keywords: clinical outcome; colorectal cancer; epigenetic regulation; histone deacetylases; histone modifications