Sessile serrated adenoma/polyp (SSA/P) is regarded as a genetically homogeneous entity, with most lesions harbouring the BRAF V600E mutation. The present study aimed to reappraise the genetic heterogeneity of SSA/Ps and its clinicopathological significance.Methods and results
We performed next-generation sequencing of 272 SSA/Ps without dysplasia and evaluated morphological and molecular features associated with the respective genotypes. BRAF V600E, BRAF non-V600E, KRAS and NRAS mutations were found in 223 (82.0%), three (1.2%), 28 (10.3%) and one lesion (0.4%), respectively. Notably, all lesions with BRAF non-V600E mutations had either KRAS or NRAS mutations concurrently. Twenty SSA/Ps (7.4%) were negative for these mutations. KRAS-mutated SSA/Ps were located more often in the distal colon (42%) compared to those with the BRAF V600E mutation (14%). Histologically, minimally serrated crypts and goblet cell-rich crypts were more common in KRAS-mutated and mutation-negative SSA/Ps. However, in most instances, SSA/Ps lacking the BRAF V600E mutation were indistinguishable morphologically from those with the BRAF V600E mutation. MUC5AC and MUC6 expression was common regardless of the mutation status, but more extensive in SSA/Ps with the BRAF V600E mutation. CpG island methylator phenotype-high was more frequent in SSA/Ps with the BRAF V600E mutation (60%), followed by mutation-negative SSA/Ps (40%) and KRAS-mutated SSA/Ps (16%).Conclusions
The present study confirmed the common presence of the BRAF V600E mutation in SSA/Ps, but also demonstrated a degree of molecular heterogeneity of SSA/Ps. SSA/Ps with and without the BRAF V600E mutation showed slightly different but overlapping histological and molecular features.