Loss of expression of the double strand break repair protein ATM is associated with worse prognosis in colorectal cancer and loss of Ku70 expression is associated with CIN
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Andrew D Beggs1,6, Enric Domingo1, Megan McGregor2, Mikael Presz2, Elaine Johnstone2, Rachel Midgley2, David Kerr3, Dahmane Oukrif4, Marco Novelli4, Muti Abulafi6, Shirley V Hodgson7, Wakkas Fadhil5, Mohammad Ilyas5, Ian PM Tomlinson1
1 Molecular & Population Genetics Laboratory and 8NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
2 Department of Oncology, University of Oxford, Level 4, Academic Block, John Radcliffe Hospital, Oxford, United Kingdom
3 Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Level 4, Academic Block, John Radcliffe Hospital, Oxford, United Kingdom
4 Department of Histopathology, Rockefeller Building, University College London, London, UK
5 Division of Pathology, School of Molecular Medical Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham, UK
6 Department of Surgery, Croydon University Hospital, Croydon, UK
7 Department of Medical Genetics, St George’s University of London, Cranmer Terrace, Tooting, London, UK
Andrew Beggs, email:
Keywords: Double strand break repair, ATM, γ-H2AX, colorectal cancer, prognosis
Received: October 04, 2012, Accepted: October 26, 2012, Published: October 28, 2012
Repair of double strand DNA breaks (DSBs) is pivotal in maintaining normal cell division and disruption of this system has been shown to be a key factor in carcinogenesis. Loss of expression of the DSB repair proteins have previously been shown to be associated with poorer survival in colorectal cancer. We wished to ascertain the relationship of altered expression of the DSB repair proteins γ-H2AX (gamma-H2AX), ATM and Ku70 with biological and clinico-pathological features of colorectal cancer. 908 tumours from the VICTOR clinical trial of stage II/III colorectal cancer were analysed for expression of γ-H2AX, ATM and Ku70 using immunohistochemistry. Expression levels were correlated with CIN and with disease-free survival, correcting for microsatellite instability, BRAF/KRAS mutation status, Dukes stage, chemo/radiotherapy, age, gender and tumour location. Down-regulated Ku70 expression was associated with chromosomal instability (p=0.029) in colorectal cancer. Reduced ATM expression was an independent marker of poor disease-free survival (HR=1.67, 95% CI 1.11-2.50, p=0.015). For Ku70, further studies are required to investigate the potential relationship of non-homologous end joining with chromosomal instability. Loss of ATM expression might serve as a biomarker of poor prognosis in colorectal cancer.
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