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

Murakami, Takashi; Mitomi, Hiroyuki; Saito, Tsuyoshi; Takahashi, Michiko; Sakamoto, Naoto; Fukui, Naoshi; Yao, Takashi; Watanabe, Sumio

doi:10.1038/modpathol.2014.41

Cited by 52 publications

(66 citation statements)

References 31 publications

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“…Methylation patterns of CRC and normal adjacent tissue samples were compared in most of the previous global methylation studies focusing on WNT signaling pathway. 20,22 Colorectal adenoma samples were involved in methylation analyses for selected WNT pathway genes 11,15,17,23,24 focusing mainly on promoter methylation level alterations. Serrated adenoma samples-representing another neoplastic pathway of CRC development-were also profiled in several previous methylation projects.…”

Section: Introductionmentioning

confidence: 99%

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

et al. 2016

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The WNT signaling pathway has an essential role in colorectal carcinogenesis and progression, which involves a cascade of genetic and epigenetic changes. We aimed to analyze DNA methylation affecting the WNT pathway genes in colorectal carcinogenesis in promoter and gene body regions using whole methylome analysis in 9 colorectal cancer, 15 adenoma, and 6 normal tumor adjacent tissue (NAT) samples by methyl capture sequencing. Functional methylation was confirmed on 5-aza-2 0 -deoxycytidine-treated colorectal cancer cell line datasets. In parallel with the DNA methylation analysis, mutations of WNT pathway genes (APC, b-catenin/CTNNB1) were analyzed by 454 sequencing on GS Junior platform. Most differentially methylated CpG sites were localized in gene body regions (95% of WNT pathway genes). In the promoter regions, 33 of the 160 analyzed WNT pathway genes were differentially methylated in colorectal cancer vs. normal, including hypermethylated AXIN2, CHP1, PRICKLE1, SFRP1, SFRP2, SOX17, and hypomethylated CACYBP, CTNNB1, MYC; 44 genes in adenoma vs. NAT; and 41 genes in colorectal cancer vs. adenoma comparisons. Hypermethylation of AXIN2, DKK1, VANGL1, and WNT5A gene promoters was higher, while those of SOX17, PRICKLE1, DAAM2, and MYC was lower in colon carcinoma compared to adenoma. Inverse correlation between expression and methylation was confirmed in 23 genes, including APC, CHP1, PRICKLE1, PSEN1, and SFRP1. Differential methylation affected both canonical and noncanonical WNT pathway genes in colorectal normal-adenoma-carcinoma sequence. Aberrant DNA methylation appears already in adenomas as an early event of colorectal carcinogenesis.

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Section: Introductionmentioning

confidence: 99%

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

et al. 2016

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“…Among the various genes involved in CRC, the Wnt signaling pathway has attracted much attention (113), as more than half of CRC cases have a β-catenin mutation (114). A recent report showed that the activation of different parts of Wnt signaling pathway may lead to development of one of two types of colorectal neoplasia: serrated or conventional adenoma/polyp (115). Accumulated research also showed that the application of Wnt signaling pathway inhibitors could greatly promote apoptosis and reduce proliferation of CRC cells (116,117).…”

Section: Wnt/β-catenin Signaling Pathwaymentioning

confidence: 99%

Notch and Wnt signaling pathway in cancer: Crucial role and potential therapeutic targets (Review)

Xiao

Xin

Tang

et al. 2015

International Journal of Oncology

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Abstract. There is no radical cure for all cancer types. The most frequently used therapies are surgical treatment, radiotherapy and chemotherapy. However, recrudescence, radiation resistance and chemotherapy resistance are the most challenging issues in clinical practice. To address these issues, they should be further studied at the molecular level, and the signaling pathways involved represent a promising avenue for this research. In the present review, we mainly discuss the components and mechanisms of activation of the Notch and Wnt signaling pathways, and we summarize the recent research efforts on these two pathways in different cancers.

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“…In this study, MLH1 promoter methylation as measured by quantitative methylation specific PCR (MethyLight), correlated tightly with the presence or absence of immunohistochemical staining. 49 This upstream methylation is postulated to be the mode of WNT pathway activation in the serrated neoplasia pathway. [49][50][51] In the current series nuclear β-catenin staining was uncommon in the ordinary SSA component, consistent with previous results, and supporting the notion that WNT signaling is not a major factor in the development of SSAs as compared to conventional adenomas.…”

Section: Discussionmentioning

confidence: 99%

“…38,47 Immunohistochemistry shows regularly expanded proliferative and luminal compartments with Ki67 and CK20 respectively. 48 p16 staining is frequently observed in the crypt bases 49,50 and MVHPs are usually positive for the mucin core proteins MUC2 and MUC5AC and variably for MUC6.…”

Section: Pathological Featuresmentioning

confidence: 99%

“…41,72 Methylation induced silencing of p16 was proposed to allow progression from MVHP to SSA via escape from oncogene-induced senescence, 73 but more recently it has been shown that loss of p16 staining coincides with development of high-grade dysplasia or invasive carcinoma, late in polyp progression. 49 38 TSAs are the least frequent serrated polyp accounting for around 1% of colorectal polyps (range 0.6-1.9%). 41,43,77 They can occur throughout the large bowel but have a predilection for the distal colon and rectum.…”

Section: Molecular Featuresmentioning

confidence: 99%

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A clinicopathological and molecular categorisation of serrated colorectal polyps

Bettington¹

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Approximately 25% of colorectal carcinomas arise via the serrated neoplasia pathway.These cancers develop in serrated type polyps. Removal of these precursor polyps before the development of malignancy offers a unique opportunity to interrupt neoplastic progression and is the rationale for colonoscopic surveillance.Serrated colorectal polyps fall into three major subtypes; namely hyperplastic polyps, sessile serrated adenomas and traditional serrated adenomas. Hyperplastic polyps are the most numerous, but have limited, if any malignant potential. Sessile serrated adenomas give rise to the majority of serrated neoplasia pathway malignancies. Although rare, traditional serrated adenomas may be more likely to progress, thus requiring closer surveillance. While both are amenable to colonoscopic removal they present unique challenges when compared to the polyps of the "traditional" colorectal cancer pathway. In particular, sessile serrated adenomas are sessile (hence the name) and difficult to detect by colonoscopy, they are frequently misdiagnosed/under-diagnosed by pathologists, resulting in inadequate surveillance and their molecular biology is incompletely understood. Thus the aims of this PhD were to address issues relating to the diagnostic criteria of serrated colorectal polyps and to better define the clinicopathological and molecular features of these lesions.To this end several study sets were established. Firstly, a cohort to address issues surrounding the diagnosis of the sessile serrated adenoma was collected. Although The second study set comprised 200 rigorously diagnosed traditional serrated adenomas.A detailed clinicopathological and molecular assessment was performed on all cases. It was found that traditional serrated adenomas segregated into two key subtypes based on their BRAF or KRAS mutation status. This important molecular distinction underscored a substantial difference in both the clinicopathological and molecular features of these polyps. In particular BRAF mutated traditional serrated adenomas arose from pre-existing sessile serrated adenomas, were more likely to be located in the proximal colon, were more likely to have a sessile growth pattern, were more likely to demonstrate the CpG island methylator phenotype and were more likely to silence CDKN2A as they progressed to carcinoma. Importantly traditional serrated adenomas of all types retained mismatch repair enzyme function, meaning that the BRAF mutated subtype is an important precursor of the very aggressive BRAF mutated, microsatellite stable subtype of colorectal carcinoma.The third study set comprised a group of tubulovillous adenomas with serrated architectural features. A detailed clinicopathological and molecular assessment of these polyps was performed and then compared to control sets of traditional serrated adenomas and conventional tubulovillous adenomas. It was found that the serrated tubulovillous adenomas could be reliably diagnosed and had features distinct from both of the control cohorts. Furthermore, they h...

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

Cited by 52 publications

References 31 publications

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

Notch and Wnt signaling pathway in cancer: Crucial role and potential therapeutic targets (Review)

A clinicopathological and molecular categorisation of serrated colorectal polyps

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