title: A further investigation of combined mismatch repair and BRAFV600E mutation specific immunohistochemistry as a predictor of overall survival in colorectal carcinoma.
abstract: Mutation specific immunohistochemistry (IHC) is a promising new technique to detect the presence of the BRAFV600E mutation in colorectal carcinoma (CRC). When performed in conjunction with mismatch repair (MMR) IHC, BRAFV600E IHC can help to further triage genetic testing for Lynch Syndrome. In a cohort of 1426 patients undergoing surgery from 2004 to 2009 we recently demonstrated that the combination of MMR and BRAFV600E IHC holds promise as a prognostic marker in CRC, particularly because of its ability to identify the poor prognosis MMR proficient (MMRp) BRAFV600E mutant subgroup. We attempted to validate combined MMR and BRAFV600E IHC as a prognostic indicator in a separate cohort comprising consecutive CRC patients undergoing surgery from 1998 to 2003. IHC was performed on a tissue microarray containing tissue from 1109 patients with CRC. The 5 year survivals stratified by staining patterns were: MMRd/BRAFwt 64%, MMRd/BRAFV600E 64%, MMRp/BRAFwt 60% and MMRp/BRAFV600E 53%. Using the poor prognosis MMRp/BRAFV600E phenotype as baseline, univariate Cox regression modelling demonstrated the following hazard ratios for death: MMRd/BRAFwt HR = 0.71 (95%CI = 0.40-1.27), p = 0.31; MMRd/BRAFV600E HR = 0.74 (95%CI = 0.51-1.07), p = 0.11 and MMRp/BRAFwt HR = 0.79 (95%CI = 0.60-1.04), p = 0.09. Although the findings did not reach statistical significance, this study supports the potential role of combined MMR and BRAF IHC as prognostic markers in CRC.
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Nathan
authors.initials: N
authors.lastname: Luey
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia; Histopath Pathology, North Ryde, NSW, Australia; Sydney Vital Translational Research Centre, Royal North Shore Hospital, Pacific Highway, St Leonards, NSW, Australia.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Toon
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia.
authors.forename: Loretta
authors.initials: L
authors.lastname: Sioson
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia; Histopath Pathology, North Ryde, NSW, Australia.
authors.forename: Adele
authors.initials: A
authors.lastname: Clarkson
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Watson
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia.
authors.forename: Carmen
authors.initials: C
authors.lastname: Cussigh
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kedziora
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Department of Colorectal Surgery, Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: Pincott
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Department of Colorectal Surgery, Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Pillinger
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Department of Colorectal Surgery, Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: Justin
authors.initials: J
authors.lastname: Evans
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Department of Colorectal Surgery, Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Percy
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Sydney Vital Translational Research Centre, Royal North Shore Hospital, Pacific Highway, St Leonards, NSW, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Engel
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: Margaret
authors.initials: M
authors.lastname: Schnitzler
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia; Sydney Vital Translational Research Centre, Royal North Shore Hospital, Pacific Highway, St Leonards, NSW, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics / Q000473:pathology; D053843:DNA Mismatch Repair / Q000235:genetics*; D005260:Female; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf