title: Immunohistochemical validation of overexpressed genes identified by global expression microarrays in adrenocortical carcinoma reveals potential predictive and prognostic biomarkers.
abstract: BACKGROUND
  Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. The aim of this study was to identify novel protein signatures that would predict clinical outcomes in a large cohort of patients with ACC based on data from previous gene expression microarray studies.
  
  
  METHODS
  A tissue microarray was generated from the paraffin tissue blocks of 61 patients with clinical outcomes data. Selected protein biomarkers based on previous gene expression microarray profiling studies were selected, and immunohistochemistry staining was performed. Staining patterns were correlated with clinical outcomes, and a multivariate analysis was undertaken to identify potential biomarkers of prognosis.
  
  
  RESULTS
  Median overall survival was 45 months, with a 5-year overall survival rate of 44%. Median disease-free survival was 58 months, with a 5-year disease-free survival rate of 44%. The proliferation marker Ki-67 and DNA topoisomerase TOP2A were associated with significantly poorer overall and disease-free survival. The results also showed strong correlation between the transcriptional repressor EZH2 and TOP2A expression, suggesting a novel role for EZH2 as an additional marker of prognosis. In contrast, increased expression of the BARD1 protein, with its ubiquitin ligase function, was associated with significantly improved overall and disease-free survival, which has yet to be documented for ACC.
  
  
  CONCLUSIONS
  We present novel biomarkers that assist in determining prognosis for patients with ACC. Ki-67, TOP2A, and EZH2 were all significantly associated with poorer outcomes, whereas BARD1 was associated with improved overall survival. It is hoped that these biomarkers may help tailor additional therapy and be potential targets for directed therapy.
authors: Kolling Institute of Medical Research, Endocrine and Oncology Surgical Unit, and Department of Anatomical Pathology, Royal North Shore Hospital, Faculty of Medicine, Northern Clinical School, and Department of Surgery, Westmead Hospital, University of Sydney, New South Wales, Australia; South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors: Julian C Y
authors: JC
authors: Ip
authors: Kolling Institute of Medical Research, Endocrine and Oncology Surgical Unit, and Department of Anatomical Pathology, Royal North Shore Hospital, Faculty of Medicine, Northern Clinical School, and Department of Surgery, Westmead Hospital, University of Sydney, New South Wales, Australia; South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors: Tony C Y
authors: TC
authors: Pang
authors: Kolling Institute of Medical Research, Endocrine and Oncology Surgical Unit, and Department of Anatomical Pathology, Royal North Shore Hospital, Faculty of Medicine, Northern Clinical School, and Department of Surgery, Westmead Hospital, University of Sydney, New South Wales, Australia; South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors: Anthony R
authors: AR
authors: Glover
authors: Kolling Institute of Medical Research, Endocrine and Oncology Surgical Unit, and Department of Anatomical Pathology, Royal North Shore Hospital, Faculty of Medicine, Northern Clinical School, and Department of Surgery, Westmead Hospital, University of Sydney, New South Wales, Australia; South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors: Patsy
authors: P
authors: Soon
authors: Kolling Institute of Medical Research, Endocrine and Oncology Surgical Unit, and Department of Anatomical Pathology, Royal North Shore Hospital, Faculty of Medicine, Northern Clinical School, and Department of Surgery, Westmead Hospital, University of Sydney, New South Wales, Australia; South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors: Jing Ting
authors: JT
authors: Zhao
authors: Kolling Institute of Medical Research, Endocrine and Oncology Surgical Unit, and Department of Anatomical Pathology, Royal North Shore Hospital, Faculty of Medicine, Northern Clinical School, and Department of Surgery, Westmead Hospital, University of Sydney, New South Wales, Australia; South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors: Stephen
authors: S
authors: Clarke
authors: Kolling Institute of Medical Research, Endocrine and Oncology Surgical Unit, and Department of Anatomical Pathology, Royal North Shore Hospital, Faculty of Medicine, Northern Clinical School, and Department of Surgery, Westmead Hospital, University of Sydney, New South Wales, Australia; South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors: Bruce G
authors: BG
authors: Robinson
authors: Kolling Institute of Medical Research, Endocrine and Oncology Surgical Unit, and Department of Anatomical Pathology, Royal North Shore Hospital, Faculty of Medicine, Northern Clinical School, and Department of Surgery, Westmead Hospital, University of Sydney, New South Wales, Australia; South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors: Anthony J
authors: AJ
authors: Gill
authors: Kolling Institute of Medical Research, Endocrine and Oncology Surgical Unit, and Department of Anatomical Pathology, Royal North Shore Hospital, Faculty of Medicine, Northern Clinical School, and Department of Surgery, Westmead Hospital, University of Sydney, New South Wales, Australia; South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia stansidhu@nebsc.com.au.
authors: Stan B
authors: SB
authors: Sidhu
mesh_terms: D018268:Adrenocortical Carcinoma / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000075223:Poly-ADP-Ribose Binding Proteins; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D012042:Registries; D015996:Survival Rate; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; D000075223:Poly-ADP-Ribose Binding Proteins; D025521:Tumor Suppressor Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human
keywords: Adrenocortical carcinoma; Biomarkers; Immunohistochemistry; Prognosis; Tissue microarray
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