Gastric-type expression signature in serrated pathway–associated colorectal tumors

Accumulating evidence has indicated that serrated pathway-associated colorectal tumors may be associated with aberrant gastric-type differentiation. Here, we investigated the immunoexpression profiles of gastric-type markers and intestinal-type markers in colorectal tumors, focusing on their relation to serrated pathway-associated tumors. Immunohistochemistry for 7 gastric-type markers (ANXA10, VSIG1, CLDN18, CTSE, TFF2, MUC5AC, and MUC6) and 2 intestinal-type markers (CDX2 and CK20) was performed in 36 normal gastric/colorectal mucosa tissues, 163 colorectal polyps, and 175 microsatellite-unstable colorectal carcinomas (MSI-H CRCs). In normal tissues, all 7 candidate gastric-type markers showed expressional specificity for normal gastric mucosa. Among the colorectal polyps, sessile serrated adenoma/polyps demonstrated the highest positive rate of ANXA10, CLDN18, MUC5AC, and MUC6 expression (87%, 35%, 61%, and 52%, respectively). Microvesicular hyperplastic polyps showed the highest frequencies of ANXA10, VSIG1, and TFF2 positivity (87%, 87%, and 67%, respectively). ANXA10 and MUC6 expression was not detected in all conventional adenomas. In MSI-H CRCs, the expression of ANXA10, TFF2, and MUC5AC was significantly associated with sporadic tumors (P < .001, P = .01, and P < .001, respectively). Moreover, all of the 7 gastric-type markers were significantly related to preferential expression in proximal colon carcinomas among MSI-H CRCs. CDX2 and CK20 expression was retained in all colorectal polyps, whereas there were significantly high frequencies of CDX2 loss (28%) and CK20 loss (29%) in sporadic tumors among MSI-H CRCs. In conclusion, the early gain of gastric differentiation and late loss of intestinal differentiation are immunophenotypic features in the serrated pathway to colorectal carcinoma.