VE1 immunohistochemistry predicts BRAF V600E mutation status and clinical outcome in colorectal cancer.
OBJECTIVE
VE1 is a monoclonal antibody detecting mutant BRAFV(600E) protein by immunohistochemistry. Here we aim to determine the inter-observer agreement and concordance of VE1 with mutational status, investigate heterogeneity in colorectal cancers and metastases and determine the prognostic effect of VE1 in colorectal cancer patients.


METHODS
Concordance of VE1 with mutational status and inter-observer agreement were tested on a pilot cohort of colorectal cancers (n = 34), melanomas (n = 23) and thyroid cancers (n = 8). Two prognostic cohorts were evaluated (n = 259, Cohort 1 and n = 226, Cohort 2) by multiple-punch tissue microarrays. VE1 staining on preoperative biopsies (n = 118 patients) was compared to expression in resections. Primary tumors and metastases from 13 patients were tested for VE1 heterogeneity using a tissue microarray generated from all available blocks (n = 100 blocks).


RESULTS
Inter-observer agreement was 100% (kappa = 1.0). Concordance between VE1 and V600E mutation was 98.5%. Cohort 1: VE1 positivity (seen in 13.5%) was associated with older age (p = 0.0175) and MLH1 deficiency (p < 0.0001). Cohort 2: VE1 positivity (seen in 12.8%) was associated with female gender (p = 0.0016), right-sided tumor location (p < 0.0001), higher tumor grade (p < 0.0001) and mismatch repair (MMR)-deficiency (p < 0.0001). In survival analysis, MMR status and postoperative therapy were identified as possible confounding factors. Adjusting for these features, VE1 was an unfavorable prognostic factor. Preoperative biopsy staining matched resections in all cases except one. No heterogeneity was found across any primary/metastatic tumor blocks.


CONCLUSIONS
VE1 is highly concordant for V600E and homogeneously expressed suggesting staining can be analysed on resection specimens, preoperative biopsies, metastatic lesions and tissue microarrays.
Translational Research Unit, Institute of Pathology, Bern University Hospital, Bern, Switzerland.
Christian
C
Schafroth
Translational Research Unit, Institute of Pathology, Bern University Hospital, Bern, Switzerland.
José A
JA
Galván
Translational Research Unit, Institute of Pathology, Bern University Hospital, Bern, Switzerland.
Irene
I
Centeno
Translational Research Unit, Institute of Pathology, Bern University Hospital, Bern, Switzerland.|Division of Clinical Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Viktor H
VH
Koelzer
Translational Research Unit, Institute of Pathology, Bern University Hospital, Bern, Switzerland.|Division of Clinical Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Heather E
HE
Dawson
Translational Research Unit, Institute of Pathology, Bern University Hospital, Bern, Switzerland.
Lena
L
Sokol
Translational Research Unit, Institute of Pathology, Bern University Hospital, Bern, Switzerland.|Division of Clinical Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Gregor
G
Rieger
Department of Medical Oncology, Bern University Hospital, Bern, Switzerland.
Martin D
MD
Berger
Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland.
Marion
M
Hädrich
Department of Surgery, Kantonsspital Baselland, Liestal, Switzerland.
Robert
R
Rosenberg
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Ulrich
U
Nitsche
Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland.
Beat
B
Schnüriger
Translational Research Unit, Institute of Pathology, Bern University Hospital, Bern, Switzerland.|Division of Clinical Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Rupert
R
Langer
Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland.|Department of Surgery, Tiefenau Hospital, Bern, Switzerland.
Daniel
D
Inderbitzin
Translational Research Unit, Institute of Pathology, Bern University Hospital, Bern, Switzerland.|Division of Clinical Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Alessandro
A
Lugli
Translational Research Unit, Institute of Pathology, Bern University Hospital, Bern, Switzerland.
Inti
I
Zlobec
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000276:immunology; D001706:Biopsy; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy; D004252:DNA Mutational Analysis; D005260:Female; D005858:Germany; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015588:Observer Variation; D010865:Pilot Projects; D011237:Predictive Value of Tests; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000276:immunology; D015203:Reproducibility of Results; D012189:Retrospective Studies; D012307:Risk Factors; D013557:Switzerland; D046888:Tissue Array Analysis; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
BRAF; Pathology Section; VE1; colorectal cancer; heterogeneity; metastasis; prognosis