Frequent β-Catenin Nuclear Labeling in Sessile Serrated Polyps of the Colorectum With Neoplastic Potential

Wu, Julie M.; Montgomery, Elizabeth A.; Iacobuzio‐Donahue, Christine A.

doi:10.1309/603uqkm7c2kelgju

Cited by 45 publications

(55 citation statements)

References 26 publications

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“…13 BRAF-activated serrated human tumors show unique patterns of DNA methylation in CpG-rich regions 10,14,15 and strong nuclear β-catenin staining, indicative of tumorassociated activation of the Wnt/β-catenin pathway. 16,17 Mice with an oncogenic BRAF V637E knock-in mutation develop generalized serrated hyperplasia, thus corroborating an initiating role for oncogenic BRAF in serrated adenoma. 18 Aging BRAF V637E knock-in mice exhibit focal tumor progression to dysplastic serrated adenoma and metastatic carcinoma.…”

Section: Introductionmentioning

confidence: 71%

“…The resulting ISC depletion was counteracted by upregulation of Wnt/β-catenin signaling by Wnt3a ligand or by small-molecule inhibition of GSK3β in organotypic culture, or by transgenic expression of stabilized β-catenin in the mouse intestine. Both high MAPK and β-catenin activity has been noted in human SSA 16,17 and in BRAF-driven serrated intestinal tumors in the mouse. 18 Our data suggest that the concomitant activation of MAPK and β-catenin could be required to assure stem cell and consequently tumor tissue maintenance during progression of SSA, and our ISC marker analysis during serrated tumor progression in the mouse is in agreement with such a model.…”

Section: Discussionmentioning

confidence: 99%

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Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

et al. 2014

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Colon cancer cells frequently carry mutations that activate the β-catenin and mitogen-activated protein kinase (MAPK) signaling cascades. Yet how oncogenic alterations interact to control cellular hierarchies during tumor initiation and progression is largely unknown. We found that oncogenic BRAF modulates gene expression associated with cell differentiation in colon cancer cells. We therefore engineered a mouse with an inducible oncogenic BRAF transgene, and analyzed BRAF effects on cellular hierarchies in the intestinal epithelium in vivo and in primary organotypic culture. We demonstrate that transgenic expression of oncogenic BRAF in the mouse strongly activated MAPK signal transduction, resulted in the rapid development of generalized serrated dysplasia, but unexpectedly also induced depletion of the intestinal stem cell (ISC) pool. Histological and gene expression analyses indicate that ISCs collectively converted to short-lived progenitor cells after BRAF activation. As Wnt/β-catenin signals encourage ISC identity, we asked whether β-catenin activity could counteract oncogenic BRAF. Indeed, we found that intestinal organoids could be partially protected from deleterious oncogenic BRAF effects by Wnt3a or by small-molecule inhibition of GSK3β. Similarly, transgenic expression of stabilized β-catenin in addition to oncogenic BRAF partially prevented loss of stem cells in the mouse intestine. We also used BRAF V637E knock-in mice to follow changes in the stem cell pool during serrated tumor progression and found ISC marker expression reduced in serrated hyperplasia forming after BRAF activation, but intensified in progressive dysplastic foci characterized by additional mutations that activate the Wnt/β-catenin pathway. Our study suggests that oncogenic alterations activating the MAPK and Wnt/β-catenin pathways must be consecutively and coordinately selected to assure stem cell maintenance during colon cancer initiation and progression. Notably, loss of stem cell identity upon induction of BRAF/MAPK activity may represent a novel fail-safe mechanism protecting intestinal tissue from oncogene activation.

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Section: Introductionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

et al. 2014

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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: 93%

“…24 Although the conventional adenoma-carcinoma pathway is associated with activation of the WNT/bcatenin signaling pathway, 15,16,18,25 any contribution to serrated neoplasia remains controversial. 13,14,22,25,26 The aim of this study was thus to elucidate the potential roles of WNT/b-catenin signaling in association with MLH1 methylation or BRAF/KRAS mutations in the serrated neoplasia pathway, in comparison with the conventional adenoma-carcinoma sequence.…”

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confidence: 99%

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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“…Wnt signaling pathway abnormalities, particularly abnormalities of b-catenin, also likely have a role in CIMP-high colorectal carcinomas, as abnormal nuclear localization of b-catenin is frequently identified in sessile serrated polyps/adenomas. 32,33 Importantly, B60-80% of CIMP-H tumors harbor mutations in BRAF, and CIMP-H tumors rarely, if ever, demonstrate KRAS mutations. 31,34 In addition, CIMP-H colorectal carcinomas often demonstrate methylation of the p16 promoter, resulting in diminished or absent p16 protein expression.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features

et al. 2012

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Recent literature suggests an increasing incidence of colorectal carcinoma in young patients. We performed a histologic, molecular, and immunophenotypic analysis of patients with sporadic early-onset (r40 years of age) colorectal carcinoma seen at our institution from the years 2000-2010 and compared these tumors to a cohort of consecutively resected colorectal carcinomas seen in patients 440 years of age. A total of 1160 primary colorectal adenocarcinomas were surgically resected for the years 2000 through 2010. Of these, 75 (6%) were diagnoses in patients r40 years of age of which 13 (17%) demonstrated abnormalities in DNA mismatch repair, 4 (5%) were in patients with known germline genetic disorders (two patients with familial adenomatous polyposis, one patient with juvenile polyposis, and one patient with Li-Fraumeni syndrome), and three patients (4%) had long-standing chronic inflammatory bowel disease. The sporadic early-onset colorectal carcinoma group comprised a total of 55 patients (55/1160, 5%) and were compared with a control group comprising 73 consecutively resected colorectal carcinomas with proficient DNA mismatch repair in patients 440 years of age. For the early-onset colorectal carcinoma group, most cases (33/55, 60%) were diagnosed between the age of 35 and 40 years of age. Compared with the control group, the early-onset colorectal carcinoma group was significantly different with respect to tumor location (Po0.007) with 80% (44/55 cases) identified in either the sigmoid colon (24/55, 44%) or rectum (20/55, 36%). Morphologically, early-onset colorectal carcinomas more frequently displayed adverse histologic features compared with the control colorectal carcinoma group such as signet ring cell differentiation (7/55, 13% vs 1/73, 1%, P ¼ 0.021), perineural invasion (16/55, 29% vs 8/73, 11%, P ¼ 0.009) and venous invasion (12/55, 22% vs 4/73, 6%, P ¼ 0.006). A precursor adenomatous lesion was less frequently identified in the early-onset colorectal carcinoma group compared with the control group (19/55, 35% vs 39/73, 53%, P ¼ 0.034). Of the early-onset colorectal carcinomas, only 2/45 cases (4%) demonstrated KRAS mutations compared with 11/73 (15%) of the control group colorectal adenocarcinomas harboring KRAS mutations, although this difference did not reach statistical significance (P ¼ 0.13). BRAF V600E mutations were not identified in the early-onset colorectal carcinoma group. No difference was identified between the two

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Frequent β-Catenin Nuclear Labeling in Sessile Serrated Polyps of the Colorectum With Neoplastic Potential

Cited by 45 publications

References 26 publications

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

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

Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features

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