Minoo P, Baker K, Goswami R, Chong G, Foulkes WD, Ruszkiewicz AR, Barker M, Buchanan D, Young J, Jass JRExtensive DNA methylation in normal colorectal mucosa in hyperplastic polyposis. Gut 55: 1467-1474

Department of Pathology, McGill University, Duff Medical Building, 3775 University Street, Montreal, Quebec H3A 2B4, Canada.
Gut (Impact Factor: 14.66). 10/2006; 55(10):1467-74. DOI: 10.1136/gut.2005.082859
Source: PubMed


Hyperplastic polyposis of the colorectum is a precancerous condition that has been linked with DNA methylation. The polyps in this condition have been distinguished from typical small hyperplastic polyps and renamed sessile serrated adenomas. Sessile serrated adenomas also occur sporadically and appear to be indistinguishable from their counterparts in hyperplastic polyposis.
The existence of distinguishing molecular features was explored in a series of serrated polyps and matched normal mucosa from patients with and without hyperplastic polyposis by assessing mutation of BRAF, DNA methylation in 14 markers (MINTs 1, 2 and 31, p16, MGMT, MLH1, RASSF1, RASSF2, NORE1 (RASSF5), RKIP, MST1, DAPK, FAS, and CHFR), and immunoexpression of MLH1.
There was more extensive methylation in sessile serrated adenomas from subjects with hyperplastic polyposis (p<0.0001). A more clearcut difference in patients with hyperplastic polyposis was the finding of extensive DNA methylation in normal mucosa from the proximal colon.
A genetic predisposition may underlie at least some forms of hyperplastic polyposis in which the earliest manifestation may be hypermethylation of multiple gene promoters in normal colorectal mucosa. Additionally, some of the heterogeneity within hyperplastic polyposis may be explained by different propensities for MLH1 inactivation within polyps.

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Available from: Rashmi S Goswami, Oct 06, 2015
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    • "Minoo et al., reported that 8 of 11 (73%) serrated adenomas and 5 of 5 associated colorectal cancers harbored a methylated RKIP promoter (Minoo et al., 2006). Interestingly, in the same study, the RKIP promoter was also methylated in 4 of 7 (57%) normal colonic mucosa indicating the potential importance of this aberration in colorectal cancer initiation (Minoo et al., 2006). Similarly, the same group reported a significant association between decreased RKIP expression and a high CpG island methylator phenotype (CIMP-H; Zlobec et al., 2011). "
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    ABSTRACT: From its discovery as a phosphatidylethanolamine binding protein in bovine brain to its designation as a physiological inhibitor of Raf kinase protein, RKIP has emerged as a critical molecule for maintaining subdued, well-orchestrated cellular responses to stimuli. The disruption of RKIP in a wide range of pathologies, including cancer, Alzheimer's disease, and pancreatitis, makes it an exciting target for individualized therapy and disease-specific interventions. This review attempts to highlight recent advances in the RKIP field underscoring its potential role as a master modulator of many pivotal intracellular signaling cascades that control cellular growth, motility, apoptosis, genomic integrity and therapeutic resistance. Specific biological and functional niches are highlighted to focus future research towards an enhanced understanding of the multiple roles of RKIP in health and disease. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 08/2013; 228(8). DOI:10.1002/jcp.24335 · 3.84 Impact Factor
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    • "Escape from senescence is achieved subsequently by the inactivation by promoter methylation of tumour suppressors controlling senescence [95], thus allowing a lesion to progress to a more proliferative neoplasm. An epigenetic field defect present in serrated polyposis would facilitate this process more readily [30] with the consequent increase in polyp numbers which define the condition. When multiple lesions are examined, serrated pathway features of BRAF mutation and CIMP demonstrate a high rate of concordance between discrete lesions in individuals with serrated polyposis [86, 87]. "
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    ABSTRACT: Serrated polyposis has only recently been accepted as a condition which carries an increased personal and familial risk of colorectal cancer. Described over four decades ago, it remains one of the most underrecognized and poorly understood of all the intestinal polyposes. With a variety of phenotypic presentations, it is likely that serrated polyposis represents a group of diseases rather than a single entity. Further, neoplastic progression in serrated polyposis may be associated with premature aging in the normal mucosa, typified by widespread gene promoter hypermethylation. From this epigenetically altered field, arise diverse polyps and cancers which show a range of molecular features. Despite a high serrated polyp count, only one-third of colorectal cancers demonstrate a BRAF V600E mutation, the molecular hallmark of the canonical serrated pathway, suggesting that though multiple serrated polyps act as a marker of an abnormal mucosa, the majority of CRC in these patients arise within lesions other than BRAF-mutated serrated polyps.
    Pathology Research International 05/2011; 2011:157073. DOI:10.4061/2011/157073
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    • "Furthermore, we found a strong association of CIMP with the presence of an activated mutant form of BRAF (BRAFV600E) [5]. Both CIMP and BRAF mutations have been reported in the earliest stages of colorectal neoplasia: CIMP in apparently normal mucosa of patients predisposed to multiple serrated polyps [9] and BRAF mutations in aberrant crypt foci [10]. "
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    ABSTRACT: A CpG island methylator phenotype (CIMP) is displayed by a distinct subset of colorectal cancers with a high frequency of DNA hypermethylation in a specific group of CpG islands. Recent studies have shown that an activating mutation of BRAF (BRAF(V600E)) is tightly associated with CIMP, raising the question of whether BRAF(V600E) plays a causal role in the development of CIMP or whether CIMP provides a favorable environment for the acquisition of BRAF(V600E). We employed Illumina GoldenGate DNA methylation technology, which interrogates 1,505 CpG sites in 807 different genes, to further study this association. We first examined whether expression of BRAF(V600E) causes DNA hypermethylation by stably expressing BRAF(V600E) in the CIMP-negative, BRAF wild-type COLO 320DM colorectal cancer cell line. We determined 100 CIMP-associated CpG sites and examined changes in DNA methylation in eight stably transfected clones over multiple passages. We found that BRAF(V600E) is not sufficient to induce CIMP in our system. Secondly, considering the alternative possibility, we identified genes whose DNA hypermethylation was closely linked to BRAF(V600E) and CIMP in 235 primary colorectal tumors. Interestingly, genes that showed the most significant link include those that mediate various signaling pathways implicated in colorectal tumorigenesis, such as BMP3 and BMP6 (BMP signaling), EPHA3, KIT, and FLT1 (receptor tyrosine kinases) and SMO (Hedgehog signaling). Furthermore, we identified CIMP-dependent DNA hypermethylation of IGFBP7, which has been shown to mediate BRAF(V600E)-induced cellular senescence and apoptosis. Promoter DNA hypermethylation of IGFBP7 was associated with silencing of the gene. CIMP-specific inactivation of BRAF(V600E)-induced senescence and apoptosis pathways by IGFBP7 DNA hypermethylation might create a favorable context for the acquisition of BRAF(V600E) in CIMP+ colorectal cancer. Our data will be useful for future investigations toward understanding CIMP in colorectal cancer and gaining insights into the role of aberrant DNA hypermethylation in colorectal tumorigenesis.
    PLoS ONE 12/2009; 4(12):e8357. DOI:10.1371/journal.pone.0008357 · 3.23 Impact Factor
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