The aim of this study was to compare BRAF and KRAS, CpG island methylator phenotype (CIMP), and
microsatellite instability (MSI) status in each of the histologic categories, including end-point
carcinomas with residual
adenoma, of the serrated
polyp neoplasia pathway and the traditional (nonserrated)
adenoma-
carcinoma sequence.
Deoxyribonucleic acid (
DNA) was extracted from the selected samples and assayed for BRAF, KRAS2 codon12, 13, CIMP using markers hMLH1, MGMT, MINT1, MINT2, p16, and MSI using an assay for BAT25 and BAT26. A BRAF mutation was present in 82% of serrated
carcinomas (SCas), 62% of serrated
adenomas (SAs), 83% of serrated
polyps with abnormal proliferation (SPAPs-syn. sessile serrated
adenoma [SSA]), 76% of microvesicular serrated
polyps (MVSPs), and was not found in any of the histologic categories of the traditional
adenoma-
carcinoma sequence. KRAS2 mutations were found in 43% of the goblet cell serrated
polyp (GCSP) category, 13% of MVSPs, 7% of SPAPs, and 24% of SAs; in 26% of large traditional
adenoma (lTAs) compared with small traditional
adenomas (
sTAs) (0/30; P<0.005) and in 37.3% of traditional
carcinomas (TCa). CIMP-H (>1 marker positive) was significantly more frequent in SPAP, SA, and SCa compared with
MVSP (P<0.05); CIMP-H was present in 10% of
sTAs but was found more frequently in lTA (44.4%; OR 7.2; P=0.007) and TCa (38.9%; OR 5.8; P=0.007). Higher CIMP levels (4 or more markers positive) were significantly more frequent in advanced categories of the serrated pathway (SAs [31%] and SCas [30%]) compared with lTAs [0%] and TCAs [3.4%] (OR 12.2; P=0.02). MSI-H was identified only in the
adenocarcinoma component of SCas (9/11) or in the contiguous SAs (3/7). The findings indicate that a BRAF mutation is a specific marker for a serrated
polyp pathway that has its origin in a hyperplastic
polyp (
MVSP) and a potential end point as MSI
carcinoma. CIMP-High (CIMP-H) develops early in this sequence and MSI-H develops late. The data provided a less complete picture of a second serrated pathway, identified by a KRAS2 mutation in SAs, but showed that the progressive stages of both iterations of the serrated
neoplasia pathway are separate and distinct from those of the traditional
adenoma-
carcinoma sequence.