Proximal colon cancers and the serrated pathway: a systematic analysis of precursor histology and BRAF mutation status.

Although the serrated neoplasia pathway is thought to give rise to the majority of sporadic microsatellite instability-high (MSI-H) colon cancer, the exact proportion of these tumors that arise from serrated precursors has not been fully studied. Tubular and tubulovillous adenomas with features of the serrated neoplasia pathway have been described, and unlike sessile serrated adenomas, these lesions lack BRAF mutations. The contribution of these adenomas to sporadic MSI-H colon cancer is unclear. To this end, we conducted an analysis of right-sided sporadic MSI-H and microsatellite stable (MSS) colon cancer, with emphasis on precursor lesions. Overall 25% (19/75) of MSI-H colon cancer had a precursor, of which only 4 were recognized histologically as arising from a sessile serrated adenoma, and the remaining were best classified as adenomas. Of the 31 (of 89) MSS colon cancers with a precursor, only 1 was a sessile serrated adenoma (P=0.06). Histological analysis of the precursor adenomas to sporadic MSI-H colon cancer demonstrated a high frequency of crypt serrations compared with MSS colon cancer (93 vs 36%, P<0.001). BRAF mutations were found in 57/75 (76%) sporadic MSI-H and 10/89 (11%) MSS colon cancers (P<0.001). Molecular analysis demonstrated BRAF mutations in 11/12 adenoma and 3/3 sessile serrated adenoma precursors adjacent to BRAF-mutated MSI-H colon cancer. Similarly, all 4 precursors to BRAF-mutated MSS colon cancer were also BRAF mutated. The presence of BRAF mutations in these adenomatous precursors suggests that they represent sessile serrated adenomas with complete cytologic dysplasia. Finally, patients with sporadic MSI-H colon cancer were more likely to harbour synchronous sessile serrated adenomas (20 vs 8%; P=0.023). This is the largest study to rigorously evaluate the precursor and synchronous lesions in patients with right-sided colon cancer. Detailed molecular and histological analysis of these lesions confirms the importance of serrated precursors in the development of sporadic MSI-H colon cancer.