title: 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.
abstract: 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.
authors.affiliation: University of Oxford, Oxford, UK. abeggs@well.ox.ac.uk
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Beggs
authors.forename: Enric
authors.initials: E
authors.lastname: Domingo
authors.forename: Megan
authors.initials: M
authors.lastname: McGregor
authors.forename: Mikael
authors.initials: M
authors.lastname: Presz
authors.forename: Elaine
authors.initials: E
authors.lastname: Johnstone
authors.forename: Rachel
authors.initials: R
authors.lastname: Midgley
authors.forename: David
authors.initials: D
authors.lastname: Kerr
authors.forename: Dahmane
authors.initials: D
authors.lastname: Oukrif
authors.forename: Marco
authors.initials: M
authors.lastname: Novelli
authors.forename: Muti
authors.initials: M
authors.lastname: Abulafi
authors.forename: Shirley V
authors.initials: SV
authors.lastname: Hodgson
authors.forename: Wakkas
authors.initials: W
authors.lastname: Fadhil
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ilyas
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
mesh_terms: D034961:Antigens, Nuclear / Q000096:biosynthesis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D014408:Biomarkers, Tumor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D043171:Chromosomal Instability; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D018572:Disease-Free Survival; D015536:Down-Regulation; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D000072200:Ku Autoantigen; D011110:Polymorphism, Genetic; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D016032:Randomized Controlled Trials as Topic; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics
chemical_list: D034961:Antigens, Nuclear; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen