Clinicopathological and molecular correlations in traditional serrated adenoma.

Abstract

Traditional serrated adenoma (TSA) is the least common type of colorectal serrated polyp, which exhibits considerable morphological and molecular diversity. We examined the spectra of alterations in MAPK and WNT pathway genes and their relationship with clinicopathological features in 128 TSAs. Sequencing analyses identifiedBRAFV600E,BRAFnon-V600E,KRAS, andNRASmutations in 77, 3, 45, and 1 lesion, respectively. Collectively, 124 lesions (97%) had mutations in MAPK pathway genes. Alterations in WNT pathway genes were identified in 107 lesions (84%), including RSPO fusions/overexpression, RNF43mutations,ZNRF3mutations,APCmutations, andCTNNB1mutations in 47, 45, 2, 13, and 2 lesions, respectively. Ten lesions (8%) harboredGNASmutations. There was significant interdependence between the altered MAPK and WNT pathway genes.RSPOfusions/overexpression was significantly associated withKRASmutations (31/47, 66%), whereas mostRNF43mutations coexisted with theBRAFV600E mutation (40/45, 89%). Histologically, extensive slit-like serration was more common in lesions with theBRAFV600E mutation (71%) and those withRNF43mutations (87%). Prominent ectopic crypt formation was more prevalent in lesions withRSPOfusions/overexpression (58%) and those with GNASmutations (100%). Our observations indicate that TSAs mostly harbor various combinations of concurrent WNT and MAPK gene alterations. The associations between genetic and morphological features suggest that the histological diversity of TSA reflects the underlying molecular heterogeneity.