Sessile serrated adenomas and classical adenomas: An epigenetic perspective on premalignant neoplastic lesions of the gastrointestinal tract

Abstract

The diagnosis of sessile serrated adenomas (SSAs) is challenging, and there is a great deal of interobserver variability amongst pathologists in differentiating SSAs from hyperplastic polyps (HPPs). The aim of this study was (i) to assess the utility of epigenetic changes such as DNA methylation in differentiating SSAs from HPPs and (ii) to identify common methylation based molecular markers potentially useful for early detection of premalignant neoplastic lesions of gastrointestinal tract. A total of 97 primary patient adenoma samples were obtained from The Johns Hopkins Hospital pathology archive with IRB approval and HIPAA compliance. We analyzed the promoter associated CpG island methylation status of 17 genes using nested multiplex methylation specific PCR (MSP). Methylation of CDX2, hMLH1 and TLR2 was detected in SSAs and SSAs with dysplasia but not in HPPs. A subset of genes including EVL, GATAs (4 and 5), HIN-1, SFRPs (1, 2, 4 and 5), SOX17 and SYNE1 were methylated frequently in all premalignant gastrointestinal adenomas including tubular adenomas, villous adenomas, SSAs and SSAs with dysplasia but infrequently in non-premalignant polyps such as HPPs. Methylation of CDX2, hMLH1 and TLR2 may be of diagnostic utility in differentiating, histologically challenging cases of SSAs from HPPs. Genes such as EVL, GATAs, HIN-1, SFRPs, SOX17 and SYNE1, which are frequently methylated in all types of tested premalignant adenomas, may be useful as biomarkers in stool-based strategies for early detection of these adenomas and CRCs in future.

Distinct WNT/β-catenin signaling activation in the serrated neoplasia pathway and the adenoma-carcinoma sequence of the colorectum

“…13,14,22,25,26 In previous reports, 18-100% of adenomas and 78% of adenocarcinomas of the colorectum displayed nuclear b-catenin immunoreactivity. 14,22,25 Various investigators have reported that nuclear b-catenin expression was observed in 0-60% of SSA/Ps, 7,9,13,14,22,25,26 43-100% of SSA/Ps with high-grade dysplasia, 9,13,14 and 60% of SSA/Ps with submucosal carcinoma. 13 Nuclear b-catenin labeling indices in our study were significantly lower in the SSA/P series than the adenoma series, suggesting that levels of WNT/b-catenin signaling activation may be different between the serrated neoplasia pathway and the conventional adenoma-carcinoma sequence.…”

“…9 SFRP1 and 2 were earlier reported to be methylated in 90-100% of SSA/Ps and those with dysplasia 9 as well as in 80-90% of conventional tubular adenomas and adenocarcinomas. 19 By contrast, SFRP4 was highly methylated in SSA/Ps (85%) and those with high-grade dysplasia (83%), 9 whereas its methylation was relatively low in conventional adenomas (24%) and adenocarcinomas (36%). 19 We also confirmed that SFRP1, 2, and 4 were methylated in most (82-100%) of the SSA/P series, but figures for SFRP4 were relatively low (37-50%) in the adenoma series.…”

“…24 Rare occurrence of BRAF mutations has been documented for conventional adenomas (0-5%), although they are frequent in SSA/Ps (50-90%). 4,[6][7][8][9][10][11][12][13] In contrast, KRAS mutations have shown to be rare in SSA/Ps (0-8%), but more common in conventional tubular adenomas (5-37%). 4,6,10,11,13 In our study, BRAF mutations were frequent (82%), whereas KRAS mutation was not detected in SSA/ Ps, with clearly contrasting results for tubular adenomas (BRAF mutation, 0%, KRAS mutation, 26%).…”

“…shown associations of SSA/P and those with dysplasia or carcinoma with methylation or loss of protein expression for DNA repair genes, ie, MLH1, 1,4,6-9 a CpG island methylator phenotype, 3,4,6,8 BRAF mutations, 3,4,[6][7][8][9][10][11][12][13][14] and a lack of genetic alterations in CTNNB1 (the gene coding for b-catenin protein). 14 This pathway is thought to be distinct from the conventional adenoma-carcinoma pathway, where adenomas progress to invasive colorectal carcinomas through the influence of a series of genetic alterations including adenomatous polyposis coli (APC) and KRAS mutations.…”

CpG island methylator phenotype and its association with malignancy in sporadic duodenal adenomas

“…[24][25][26] In CRC, CIMP positivity (CIMP+) has been associated with older age, female sex, proximal colon lesions, mucinous tumors, poor differentiation, microsatellite instability and BRAF mutations. 15,27,28 In serrated and adenomatous colorectal polyps, CIMP+ correlates with large size, right-sided location, and amount of villous component within the adenomas. 16 CIMP+ has also been described in small bowel carcinomas including those of the duodenum.…”