The promoter methylation status of the DNA repair gene O 6 -methylguanine-DNA methyltransferase in ulcerative colitis

Matsumura, Shunji; Oue, Naohide; Ito, Reiko; Nakayama, Hirofumi; Kitadai, Yasuhiko; Yokozaki, Hiroshi; Chayama, Kazuaki; Yasui, Wataru

doi:10.1007/s00428-003-0877-0

Cited by 26 publications

(10 citation statements)

References 17 publications

(24 reference statements)

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“…Moreover, methylation of MGMT, hMLH1 and p16, have been demonstrated in chronically inflamed mucosa in IBD patients without dysplasia. 11,12,22 Thus, it is possible that the ''field defect'' that exists in HSPS may also occur in a subset of patients with IBD. Finally, serrated polyps in patients with HSPS typically reveal a high incidence of BRAF (43%), and a low incidence (7%) of KRAS, mutations.…”

Section: Discussionmentioning

confidence: 98%

Hyperplastic/Serrated Polyposis in Inflammatory Bowel Disease

Srivastava

Redston

Farraye

et al. 2008

American Journal of Surgical Pathology

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Herein, we describe the clinical, pathologic, immunohistochemical, and molecular features of 3 unique patients with long standing inflammatory bowel disease, all of whom developed numerous discrete hyperplastic/serrated colonic polyps similar to those described in the hyperplastic/serrated polyposis syndrome. The 3 patients (2 with ulcerative colitis and 1 with Crohn ileo-colitis) were evaluated for a variety of clinical, histologic (including the type, location and number of polyps in the colon), and immunohistochemical features [MLH-1, MSH-2, MGMT (O(6)-methylguanine-DNA methyltransferase), beta-catenin, and p53]. KRAS and BRAF mutation analysis was also performed on a subset of polyps from 2 patients. All patients had moderate-severe pancolitis of more than 10 years duration and had >20 colonic polyps. None had polyps in the upper gastrointestinal tract. Pathologically, a combination of conventional hyperplastic polyps and sessile serrated polyps (adenomas) were present in the 3 cases. In addition, serrated adenomas were present in 2 and conventional adenomas in 1. Two patients also had synchronous adenocarcinoma. All 3 cases showed retention of MLH-1 and MSH-2, and a membranous beta-catenin staining pattern. However, 2 cases showed loss of MGMT in several serrated polyps, and one also in adjacent colitic mucosa. KRAS mutations were detected in 5/11 serrated polyps. However, BRAF mutations were not present in any of the polyps tested. These findings suggest the possibility of a serrated pathway of carcinogenesis in inflammatory bowel disease characterized by silencing of MGMT, most likely by gene promoter methylation, KRAS mutations, and possibly other, as yet, uncharacterized molecular alterations, resulting eventually in progression to adenocarcinoma.

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Section: Discussionmentioning

confidence: 98%

Hyperplastic/Serrated Polyposis in Inflammatory Bowel Disease

Srivastava

Redston

Farraye

et al. 2008

American Journal of Surgical Pathology

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“…Similarly, genome-wide mRNA and microRNA expression profiles differ substantially in IBD-associated and sporadic CRC 38–45 . Moreover, the broad patterns of gene hypermethylation have been shown to be similar 46–51 or different 37, 52–54 between IBD-associated and sporadic colorectal tumors. These molecular pathologic differences and similarities imply that pathways underlying malignant progression in the two conditions share certain commonalities, but are also largely unique.…”

Section: Introductionmentioning

confidence: 99%

Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease−Associated Colorectal Cancers

et al. 2016

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BACKGROUND & AIMS A long duration of inflammatory bowel disease (IBD) increases the risk for colorectal cancer (CRC). Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD. We performed whole-exome sequencing analyses to characterize the genetic landscape of these tumors. METHODS We collected colorectal tumor and non-neoplastic tissues from 31 patients with IBD and CRC (15 with ulcerative colitis, 14 with Crohn’s disease, and 2 with indeterminate colitis) and performed whole-exome sequencing analyses of the micro-dissected tumor and matched non-tumor tissues. We identified somatic alterations by comparing matched specimens. The prevalence of mutations in sporadic colorectal tumors was obtained from previously published exome-sequencing studies. RESULTS Two specimens had somatic mutations in the DNA-proofreading or mismatch repair genes POLE, MLH1, and MSH6 and the tumor cells had a hypermutable phenotype. The remaining tumors had, on average, 71 alterations per sample. TP53 was the most commonly mutated gene, with and incidence prevalence similar to that of sporadic colorectal tumors (63% of cases). However, tumors from the patients with IBD had a different mutation spectrum. APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors (13% and 20% of cases, respectively). Several genes were mutated more frequently or uniquely in tumors from patients with IBD, including SOX9 and EP300 (which encode proteins in the WNT pathway), NRG1 (which encodes an ERBB ligand), and IL16 (which encodes a cytokine). Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network, indicating a role for non-canonical WNT signaling in development of colorectal tumors in patients with IBD. CONCLUSIONS Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors. These findings could be used to develop disease-specific markers for diagnosis and treatment of patients with IBD and CRC.

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“…The difference of clinicopathological feature of colorectal cancer associated with UC from sporadic cancer often comes up for discussion. Matsumura et al reported that methylation of a DNA repair gene O 6 -methylguanine-DNA methyltransferase (MGMT) is rare in UC-associated colorectal cancer, but in sporadic cancer, in contrast, it is rather common (Matsumura et al, 2003). On the other hand, Osborn et al reported that the eyes absent 4 gene (EYE4) is hypermethylated both in sporadic and in UC-associated colorectal cancer (Osborn et al, 2006).…”

Section: Resultsmentioning

confidence: 92%

DNA hypermethylation in colorectal neoplasms and inflammatory bowel disease: a mini review

et al. 2006

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DNA hypermethylation is one of major epigenetic changes. Hypermethylation of many genes has been reported to be related with carcinogenesis and tumor progression of colorectal cancer. Some genes including estrogen receptor is associated with ageing, and changes related with ageing may be accelerated in inflammatory bowel disease. Furthermore, fecal DNA methylation will be able to be used as a marker of colorectal cancer and inflammatory bowel disease. Evaluation of hypermethylation potentially contributes diagnosis of colorectal diseases.

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The promoter methylation status of the DNA repair gene O 6 -methylguanine-DNA methyltransferase in ulcerative colitis

Cited by 26 publications

References 17 publications

Hyperplastic/Serrated Polyposis in Inflammatory Bowel Disease

Hyperplastic/Serrated Polyposis in Inflammatory Bowel Disease

Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease−Associated Colorectal Cancers

DNA hypermethylation in colorectal neoplasms and inflammatory bowel disease: a mini review

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