Sessile Serrated Polyps are Precursors of Colon Carcinomas With Deficient DNA Mismatch Repair

Abstract

We investigated whether sessile serrated adenomas/polyps (SSA/Ps) are direct precursors of colorectal carcinomas. We identified colon carcinomas that arose from SSA/Ps among 2646 colorectal cancers included in the surgical pathology database at the Mayo Clinic (2006-2012). Molecular features of the serrated neoplasia pathway were analyzed in these tumors by immunohistochemical analyses of mutant BRAF (V600E) and MLH1 proteins. Among the 33 identified SSA/P-associated colonic adenocarcinomas (median patient age, 75 y), 24 developed in women (73%), 31 were located in the proximal colon (94%), and 23 (69%) were TNM stage I or II. Thirty-one of the tumors (94%) expressed mutant BRAF; of these, 26 also had loss of MLH1 (79%), indicating deficient DNA mismatch repair of sporadic origin. Twenty-two of the tumors (67%) were interval cancers that were more common in women and did not differ significantly in TNM stage, BRAF mutation, or loss of MLH1. By histopathology, SSA/Ps that were associated with colon carcinomas contained frequent dysplasia (48%). Most cancers that arose from SSA/Ps were located on the right side of the colon and had mutant BRAF and loss of MLH1. These findings indicate that SSA/Ps are precursors of most sporadic colon carcinomas with deficient DNA mismatch repair.

Keywords: Colon Cancer; Genetics; MMR; Progression.

Figure 1

Carcinoma arising within an SSA/P. Inset shows serrated polyp to dysplasia to carcinoma pathway (star indicates SSA/P, quad arrow shows dysplastic component, arrow labels carcinoma).

Figure 2

A–C shows MSI cancer arising in SSA/P with BRAF mutant protein expression in SSA/P and cancer with MLH1 loss. D–F shows a microsatellite stable cancer arising in an SSA/P that expresses mutant BRAF and MLH1 proteins.