Serrated polyps of the large intestine: a molecular study comparing sessile serrated adenomas and hyperplastic polyps

Sandmeier, Dominique; Benhattar, Jean; Martin, Patricia; Bouzourène, Hanifa

doi:10.1111/j.1365-2559.2009.03356.x

Cited by 58 publications

(40 citation statements)

References 43 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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%).…”

Section: Modern Pathology (2015) 28 146-158mentioning

confidence: 99%

“…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.…”

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

et al. 2015

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Sessile serrated adenoma/polyp (SSA/P) is considered as an early precursor in the serrated neoplasia pathway leading to colorectal cancer development. The conventional adenoma-carcinoma sequence is associated with activation of the WNT signaling pathway, although its role in serrated lesions is still controversial. To clarify differences in WNT signaling activation in association with MLH1 methylation or BRAF/KRAS mutations between serrated and conventional routes, we performed b-catenin immunostaining, methylation-specific PCR for MLH1 and WNT signaling associated genes such as AXIN2, APC, and MCC and secreted frizzled-related proteins (SFRPs), and direct sequencing of BRAF/KRAS in 27 SSA/Ps, 14 SSA/Ps with high-grade dysplasia and 9 SSA/Ps with submucosal carcinoma, as well as 19 conventional adenomas, 26 adenomas with high-grade dysplasia and 25 adenomas with submucosal carcinoma. Nuclear b-catenin labelings were significantly lower in the serrated series than in their adenoma counterparts, and a significant increment in those labelings was found from SSA/Ps to those with high-grade dysplasia or submucosal carcinoma. The frequency of MLH1 and SFRP4 methylation was significantly higher in SSA/P series, as compared with corresponding adenoma series. AXIN2 and MCC were more frequently methylated in SSA/Ps with high-grade dysplasia and those with submucosal carcinoma than in adenoma counterparts. Stepwise increment of AXIN2 and MCC methylation was identified from SSA/Ps through those with high-grade dysplasia to those with submucosal carcinoma. A significant correlation was seen between nuclear b-catenin expression and methylation of AXIN2 or MCC in the SSA/P series. BRAF mutation was more frequent, whereas KRAS mutation was less frequent in the SSA/P series as compared with the adenoma series. There was an inverse association of BRAF mutation with AXIN2 methylation in SSA/P series. In conclusion, WNT/b-catenin signal activation mediated by the methylation of SFRP4, MCC, and AXIN2 may make different contributions to colorectal neoplasia between the serrated and conventional routes.

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Section: Discussionmentioning

confidence: 99%

Section: Modern Pathology (2015) 28 146-158mentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2015

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“…28 Because HPs and SSAs are common findings in HPS and have been shown to be difficult to differentiate microscopically, all serrated polyps were included in the criteria. [31][32][33][34] Patients with a known germline APC mutation or a bi-allelic MUTYH mutation were excluded from the study. The study was conducted in accordance with the research code of the institutional medical ethical committee on human experimentation of the Academic Medical Center and in agreement with the Helsinki Declaration of 1975 as revised in 1983.…”

Section: Patientsmentioning

confidence: 99%

A Serrated Colorectal Cancer Pathway Predominates over the Classic WNT Pathway in Patients with Hyperplastic Polyposis Syndrome

Boparai

Dekker

Polak

et al. 2011

The American Journal of Pathology

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Hyperplastic polyposis syndrome (HPS) is character-ized by the presence of multiple colorectal serrated polyps and is associated with an increased colorectal cancer (CRC) risk. The mixture of distinct precursor lesion types and malignancies in HPS provides a unique model to study the canonical pathway and a proposed serrated CRC pathway in humans. To establish which CRC pathways play a role in HPS and to obtain new support for the serrated CRC pathway, we assessed the molecular characteristics of polyps (n ‫؍‬ 84) and CRCs (n ‫؍‬ 19) in 17 patients with HPS versus control groups of various sporadic polyps (n ‫؍‬ 59) and sporadic microsatellite-stable CRCs (n ‫؍‬ 16). In HPS and sporadic polyps, APC mutations were exclusively identified in adenomas, whereas BRAF mutations were confined to serrated polyps. Six of 19 HPS CRCs (32%) were identified in a serrated polyp. Mutation analysis performed in the CRC and the serrated component of these lesions showed identical BRAF mutations. One HPS CRC was located in an adenoma, both components harboring an identical APC mutation. Overall, 10 of 19 HPS CRCs (53%) carried a BRAF mutation versus none in control group CRCs (P ‫؍‬ 0.001). Six BRAF-mutated HPS CRCs (60%) were microsatellite unstable owing to MLH1 methylation. These findings provide novel supporting evidence for the existence of a predominant serrated CRC pathway in HPS, generating microsatellite-stable and microsatellite-instable CRCs.

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“…However, there are few analyses focussing on p16 Ink4a . Up to now it is known that the expression of p16 Ink4a is upregulated in hyperplastic polyps and sessile serrated adenomas 19 and that promoter methylation of CDKN2A can be observed in serrated carcinomas. 20,21 Our work is the first comprehensive analysis of the expression and promoter methylation of CDKN2A in the spectrum of serrated lesions of the colon with BRAF mutation.…”

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Up and downregulation of p16Ink4a expression in BRAF-mutated polyps/adenomas indicates a senescence barrier in the serrated route to colon cancer

et al. 2011

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P16Ink4a is an important factor in carcinogenesis and its expression can be linked to oncogene-induced senescence. Oncogene-induced senescence is characterized by growth arrest and occurs as a consequence of oncogene activation due to KRAS or BRAF mutation. It has been shown that the induction of p16 Ink4a in premalignant lesions and its loss during malignant transformation is an important mechanism in the carcinogenesis of several tumours. Loss of p16 Ink4a is often caused by CDKN2A promoter hypermethylation. This mechanism of gene silencing is associated with the CpG island methylator phenotype (CIMP) in colorectal carcinomas, which is characterized by widespread promoter methylation. In particular, colorectal carcinomas with BRAF mutations have been shown to be strongly associated with CIMP. Also, BRAF mutations are strongly correlated with the serrated route to colorectal cancer. In this study, we investigated p16 Ink4a expression and promoter methylation in BRAF-mutated serrated lesions of the colon. P16 Ink4a expression was found to be upregulated in premalignant lesions and was lost in invasive serrated carcinomas. P16 Ink4a expression and Ki67 expression were mutually exclusive, indicating that p16 Ink4a acts as cell cycle inhibitor. Additionally, progression of malignant transformation in serrated lesions was accompanied by increasing methylation of the CDKN2A promoter. Therefore, our data provide evidence for oncogene-induced senescence in the serrated route to colorectal cancer with BRAF mutation and upregulation of p16 Ink4a expression appears to be a useful indicator of induction of senescence. Loss of p16 Ink4a expression occurs during malignant transformation and is caused mainly by aberrant methylation of the CDKN2A promoter.

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Serrated polyps of the large intestine: a molecular study comparing sessile serrated adenomas and hyperplastic polyps

Abstract: HPs and SSAs may be related lesions. However, at least right-sided SSAs differ from left-sided SSAs and HPs in the occurrence of MLH1 and p16 methylation, supporting the hypothesis that SSAs could be precursors of serrated adenocarcinomas.

Cited by 58 publications

References 43 publications

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

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

A Serrated Colorectal Cancer Pathway Predominates over the Classic WNT Pathway in Patients with Hyperplastic Polyposis Syndrome

Up and downregulation of p16Ink4a expression in BRAF-mutated polyps/adenomas indicates a senescence barrier in the serrated route to colon cancer

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