Abstract
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. 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). 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. VE1 is highly concordant for V600E and homogeneously expressed suggesting staining can be analysed on resection specimens, preoperative biopsies, metastatic lesions and tissue microarrays.
Highlights
The BRAF proto-oncogene is a serine-threonine kinase that is mutated in approximately 10% of colorectal cancers [1]
sessile serrated adenomas (SSA) may eventually develop into colorectal cancers with a high-degree of microsatellite instability (MSI-H); BRAFV600E mutations are over-represented in this group with a frequency of 40-60% [1]
BRAFV600E is used as an exclusion criteria in the case of suspected Lynch syndrome, as this mutation does not appear in Lynch syndrome patients with the MSI-H phenotype caused by germline mutations in factors of the mismatch repair (MMR) system [3]
Summary
The BRAF proto-oncogene is a serine-threonine kinase that is mutated in approximately 10% of colorectal cancers [1]. The most common mutation is a thymidineadenine transversion in the kinase domain of the protein resulting in a V600E amino acid. This leads to constitutive www.impactjournals.com/oncotarget activation of MAPK signaling and to cell growth and proliferation. Concerning the molecular classification of colorectal cancer and tumorigenesis, BRAF mutation is an early event hypothesized to give rise by way of oncogeneactivated senescence to the development of sessile serrated adenomas (SSA) and to the hypermethylator phenotype [2]. SSA may eventually develop into colorectal cancers with a high-degree of microsatellite instability (MSI-H); BRAFV600E mutations are over-represented in this group with a frequency of 40-60% [1]. BRAFV600E is used as an exclusion criteria in the case of suspected Lynch syndrome, as this mutation does not appear in Lynch syndrome patients with the MSI-H phenotype caused by germline mutations in factors of the mismatch repair (MMR) system [3]
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