Mapping of DOG1 expression in colorectal carcinomas

Discovery on Gastrointestinal stromal tumour (DOG1) could deliver mitogen/survival signalling in colorectal carcinoma (CRC) cell lines. DOG1 is a major calcium-activated chloride channel expressed in mesenchymal and epithelial cells where it governs secretion of fluid and mucus. This study details DOG1 expression in various histopathological subtypes of CRC and assesses the relationship between DOG1 expression and an immunophenotype based on the secreted gel-forming mucins, as well as molecular groups of CRCs. A selection of 93 CRCs was analysed for clinicopathological data, RAS and BRAF mutations, microsatellite instability status, and mismatch-repair proteins (MLH1, MSH2, MSH6, PMS2). Their DOG1, MUC2, MUC5AC, MUC6, CDX2, keratin-20, and keratin-7 immunoprofiles were then compared with histopathology and molecular features of CRC. The prognostic relevance of DOG1 was assessed using univariate and multivariate survival analyses. DOG1 was detected in neoplastic cells and cancer-associated fibroblasts (CAFs) of 45 and 41 CRCs, respectively. In a clustering study, high expression of DOG1 in neoplastic cells was found in (i) various histological subtypes of adenocarcinomas with a gastric-like phenotype, BRAF mutation, and microsatellite instability high (MSI-H) and (ii) adenocarcinomas with a mucinous component, KRAS mutation, and microsatellite stability status (MSS). CAF DOG1 expression was identified in MSS conventional adenocarcinomas. DOG1 expression in tumour cells was associated with no benefit from adjuvant chemotherapy. DOG1-positive CAFs were associated with better overall survival. This study suggests that DOG1 expression is detected in a high proportion of CRC because it is expressed in neoplastic cells of various histological subtypes of CRC that secrete gel-forming mucins, independently of mucinous features or in CAFs of conventional adenocarcinomas.