Colorectal serrated adenocarcinoma shows a different profile of oncogene mutations, MSI status and DNA repair protein expression compared to conventional and sporadic MSI-H carcinomas

Abstract

Molecular characterization has been extensively studied in serrated polyps but very little is known in serrated adenocarcinomas (SACs). We analyzed the incidence of KRAS, BRAF and PIK3CA mutations, microsatellite instability (MSI) status and loss of the DNA repair proteins MLH1, MSH2, MSH6 and MGMT in a series of 89 SAC, 81 matched conventional carcinomas (CC) and 13 sporadic colorectal cancer showing histological and molecular features of high-level MSI (sMSI-H). Our results demonstrate that KRAS are more prevalent than BRAF mutations in SAC (42.7% vs. 25.8%; p = 0.011) being the KRAS-mutated cases even more abundant in SAC displaying adjacent serrated adenomas (51%). G12D and E545K are the most common KRAS and PIK3CA mutations found in SAC, respectively. SAC show higher frequency of MGMT loss compared to CC (50.6% vs. 25.3%; p = 0.001) especially in distal colon/rectum (60.0% vs. 21.6%; p = 0.0009). SAC differ from sMSI-H in terms of KRAS and BRAF mutation prevalence, MSI status and MLH1 expression (p = 0.0003, p < 0.0001, p < 0.0001, p < 0.001, respectively). SACs are more often KRAS-mutated and microsatellite stable and display different molecular and immunohistochemical characteristics compared to CC and sMSI-H.