Clinicopathological and molecular correlations in traditional serrated adenoma.

Background: Traditional serrated adenoma (TSA) is the least common type of colorectal serrated polyp, which exhibits considerable morphological and molecular diversity.

Methods: We examined the spectra of alterations in MAPK and WNT pathway genes and their relationship with clinicopathological features in 128 TSAs.

Results: Sequencing analyses identified BRAF V600E, BRAF non-V600E, KRAS, and NRAS mutations 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, RNF43 mutations, ZNRF3 mutations, APC mutations, and CTNNB1 mutations in 47, 45, 2, 13, and 2 lesions, respectively. Ten lesions (8%) harbored GNAS mutations. There was significant interdependence between the altered MAPK and WNT pathway genes. RSPO fusions/overexpression was significantly associated with KRAS mutations (31/47, 66%), whereas most RNF43 mutations coexisted with the BRAF V600E mutation (40/45, 89%). Histologically, extensive slit-like serration was more common in lesions with the BRAF V600E mutation (71%) and those with RNF43 mutations (87%). Prominent ectopic crypt formation was more prevalent in lesions with RSPO fusions/overexpression (58%) and those with GNAS mutations (100%).

Conclusions: 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.