title: Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair.
abstract: BACKGROUND
  Despite intensive research into the molecular abnormalities associated with colorectal cancer (CRC), no diagnostic tests have emerged which usefully complement standard histopathological assessments.
  
  
  OBJECTIVE
  To assess the feasibility of using immunohistochemistry to detect replication error (RER) positive CRCs and determine the incidence of RER positivity within distinct patient subgroups.
  
  
  METHODS
  502 CRCs were analysed for RER positivity (at least two markers affected) and/or expression of hMSH2 and hMLH1.
  
  
  RESULTS
  There were 15/30 (50%) patients with metachronous CRCs, 16/51 (31%) with synchronous CRCs, 14/45 (31%) with a proximal colon carcinoma, and 4/23 (17%) who developed a CRC under the age of 50 showed RER positivity. However, 0/54 patients who developed a solitary carcinoma of the rectum/left colon over the age of 50 showed RER positivity. Immunohistochemical analysis revealed that 66/66 (100%) RER positive carcinomas were associated with complete lack of expression of either hMSH2 or hMLH1. This correlation was confirmed using a further 101 proximal colon carcinomas. Patients with a mismatch repair defective carcinoma showed improved survival but a 5.54 times relative risk of developing a metachronous CRC. A prospective immunohistochemical study revealed 13/117 (11%) patients had a mismatch repair defective carcinoma. A fivefold excess of hMLH1 defective cases was noted.
  
  
  CONCLUSIONS
  All RER positive carcinomas were identified by the immunohistochemical test. This is the first simple laboratory test which can be performed routinely on all CRCs. It will provide a method for selecting patients who should be investigated for HNPCC, offered long term follow up, and who may not respond to standard chemotherapy regimens.
authors.affiliation: Molecular Oncology, Algernon Firth Institute of Pathology, School of Medicine, University of Leeds, Leeds, UK.
authors.forename: L
authors.initials: L
authors.lastname: Cawkwell
authors.forename: S
authors.initials: S
authors.lastname: Gray
authors.forename: H
authors.initials: H
authors.lastname: Murgatroyd
authors.forename: F
authors.initials: F
authors.lastname: Sutherland
authors.forename: L
authors.initials: L
authors.lastname: Haine
authors.forename: M
authors.initials: M
authors.lastname: Longfellow
authors.forename: S
authors.initials: S
authors.lastname: O'Loughlin
authors.forename: D
authors.initials: D
authors.lastname: Cross
authors.forename: O
authors.initials: O
authors.lastname: Kronborg
authors.forename: C
authors.initials: C
authors.lastname: Fenger
authors.forename: N
authors.initials: N
authors.lastname: Mapstone
authors.forename: M
authors.initials: M
authors.lastname: Dixon
authors.forename: P
authors.initials: P
authors.lastname: Quirke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005240:Feasibility Studies; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein