title: RAD21 cohesin overexpression is a prognostic and predictive marker exacerbating poor prognosis in KRAS mutant colorectal carcinomas.
abstract: BACKGROUND
  RAD21 is a component of the cohesion complex and is integral to chromosome segregation and error-free DNA repair. RAD21 is functionally important in tumour progression but its role in colorectal carcinoma (CRC) is unclear. We therefore assessed its clinicopathological and prognostic significance in CRC, as well as its effect on chemosensitivity.
  
  
  METHODS
  A retrospective observation study examined RAD21 expression in 652 CRCs using a tissue microarray approach. Correlation with clinicopathological factors including gender, tumour grade, mucinous subtype, TNM stage, disease-specific survival (DSS), BRAF and KRAS mutation status, tumour p53 immunostaining, tumour microsatellite instability and tumour CpG island methylator phenotype was performed. Colorectal cancer cell clones with stable RAD21 knockdown were generated and tested for cellular sensitivity to conventional chemotherapeutic drugs.
  
  
  RESULTS
  RAD21 expression was significantly correlated with male gender (56.7% vs 43.3%, P=0.02), well-differentiated histology (14.4% vs 4.0%, P=0.0001), higher T-stage (36.1% vs 27.0%, P=0.01), presence of metastasis (18.8% vs 12.6%, P=0.03), and shorter DSS (hazard ratio (HR) 1.4, 95% CI 1.1 to 1.9, P=0.01) in both univariate and multivariate analysis. RAD21 expression was associated with shorter DSS in patients with KRAS mutant tumours (HR:2.6, 95% CI:1.4-4.3, P=0.001) and in patients receiving adjuvant chemoradiotherapy (HR:1.9, 95% CI:1.2-3.0, P=0.008). Colorectal cancer cells with RAD21 knockdown exhibited enhanced sensitivity to 5-fluorouracil, either alone or in combination with oxaliplatin.
  
  
  CONCLUSIONS
  RAD21 expression in CRC is associated with aggressive disease especially in KRAS mutant tumours and resistance to chemoradiotherapy. RAD21 may be an important novel therapeutic target.
authors.affiliation: 1] Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Department of Oncology and Department of Pathology, The University of Melbourne, Parkville, Victoria 3000, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Deb
authors.affiliation: 1] Sir Peter MacCallum Department of Oncology and Department of Pathology, The University of Melbourne, Parkville, Victoria 3000, Australia [2] Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Colorectal Surgery, Oxford University Hospitals, Oxford Cancer Centre, Churchill Hospital, Oxford, Ox3 7LJ, UK.
authors.forename: J
authors.initials: J
authors.lastname: Tuynman
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: J
authors.initials: J
authors.lastname: George
authors.affiliation: Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Bioinformatics, Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: R L
authors.initials: RL
authors.lastname: Ward
authors.affiliation: Department of Colorectal Surgery, Oxford University Hospitals, Oxford Cancer Centre, Churchill Hospital, Oxford, Ox3 7LJ, UK.
authors.forename: N
authors.initials: N
authors.lastname: Mortensen
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: N J
authors.initials: NJ
authors.lastname: Hawkins
authors.affiliation: North Coast Cancer Institute, University of Sydney, Lismore, New South Wales 2480, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: McKay
authors.affiliation: 1] Sir Peter MacCallum Department of Oncology and Department of Pathology, The University of Melbourne, Parkville, Victoria 3000, Australia [2] Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: R G
authors.initials: RG
authors.lastname: Ramsay
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: S B
authors.initials: SB
authors.lastname: Fox
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D018797:Cell Cycle Proteins; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D012737:Sex Factors; D046888:Tissue Array Analysis; D018631:ras Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C117307:KRAS protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C429022:RAD21 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins