Genetic Alterations in Ulcerative Colitis‐associated Neoplasia Focusing on APC, K‐ras Gene and Microsatellite Instability

Umetani, Naoyuki; Sasaki, Shin; Watanabe, Toshiaki; Shinozaki, Masaru; Matsuda, Keiji; Ishigami, Hironori; Ueda, Etsuko; Muto, Tetsuichiro

doi:10.1111/j.1349-7006.1999.tb00681.x

Cited by 69 publications

(48 citation statements)

References 39 publications

(56 reference statements)

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“…Flat adenomas have been characterized as an important precursor to colorectal carcinoma (Rembacken et al, 2000). These lesions have a low frequency of Kras gene mutation (Jass, 1995), as does dysplasia complicating chronic inflammatory bowel disease in the form of ulcerative colitis and Crohn colitis, in which MSI-H is relatively common (Umetani et al, 1999). Our finding that K-ras gene mutation is infrequent in Egyptian colorectal carcinomas unassociated with schistosomiasis raises the possibility that the flat adenoma could be an important precursor.…”

Section: Discussionmentioning

confidence: 79%

Contrasting molecular pathology of colorectal carcinoma in Egyptian and Western patients

et al. 2001

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Summary Colorectal carcinoma is uncommon in Egypt, but a high proportion of cases occurs before age 40 years and in the rectum. We compared the molecular pathology of 59 representative Egyptian patients aged 10-72 to Western patients with sporadic, young-onset, or hereditary non-polyposis colorectal cancer syndrome (HNPCC)-associated carcinoma and found significant differences. Most Egyptian cancers were rectal (51%) and poorly differentiated (58%). High levels of microsatellite instability (MSI-H) were frequent (37%) and attributable in some cases (36%) to methylation of the promoter of the hMLH1 mismatch repair gene, but no MSI-H cancer had loss of hMSH2 mismatch repair gene product of the type seen with germline hMSH2 mutation in HNPCC. K-ras mutation was uncommon (11%). In subset analyses, high frequencies of MSI-H in rectal carcinomas (36%) and p53 gene product overexpression in MSI-H cancers (50%) were found. MSI-H and K-ras mutation in Egyptians under age 40 were unusual (17% and 0%, respectively), and schistosomiasis was associated with MSI and K-ras mutation. Cluster analysis identified 2 groups: predominantly young men with poorly differentiated mucinous and signet-ring cell colorectal carcinoma lacking K-ras mutation; older patients who had well-or moderately differentiated adenocarcinoma often with MSI-H, K-ras mutation and schistosomiasis. Our findings show that the molecular pathology of colorectal cancer in older as well as younger Egyptians has unique differences from Western patients, and schistosomiasis influences the molecular pathogenesis of some tumours.

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Section: Discussionmentioning

confidence: 79%

Contrasting molecular pathology of colorectal carcinoma in Egyptian and Western patients

et al. 2001

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“…MGMT methylation may not serve as a [29] maker to predict premalignant condition in non-neoplastic-looking mucosa in UC. Some studies have reported the relationship between MSI status and UC-associated CRC [15,28]. A high incidence of the MSI in long-standing UC with severe inflammation probably reflects genomic instability caused by repeated inflammation stress [15].…”

Section: Discussionmentioning

confidence: 98%

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

et al. 2003

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Patients with long-standing and extensive ulcerative colitis (UC) have an increased incidence of colorectal cancer (CRC). It has been reported that a DNA repair gene, O6-methylguanine-DNA methyltransferase (MGMT) is inactivated by promoter hypermethylation in sporadic CRCs. Hence, we investigated the promoter methylation status of MGMT by methylation specific polymerase chain reaction (PCR) in a total of 67 tissue samples (61 non-cancerous tissues and 6 cancer tissues) from 24 patients with UC. Promoter hypermethylation of MGMT was detected in one well-differentiated adenocarcinoma (16.7%) of 6 cancer samples and not detected in any of adenomas and dysplasias. In non-dysplastic tissues, promoter hypermethylation of MGMT was detected in 2 (3.7%, mucosa with mild inflammation) of 54 samples. The frequency of MGMT promoter hypermethylation in UC-associated CRCs found in this study (16.7%) is obviously lower than previously reported in sporadic CRCs (39.0-42.0%). We also confirmed that 42.9% (6/14) of sporadic CRCs showed the promoter methylation. These findings indicated that promoter hypermethylation of the MGMT gene is infrequent in patients with UC, and may not closely contribute to UC-associated colorectal tumorigenesis. A different genetic pathway for tumor progression may exist between sporadic CRC and UC-associated CRC.

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“…However, the reported frequency of MSI-H has varied from 9 to 50%. 17,20,21 MSI has also been reported in colorectal epithelium of UC patients suffering from chronic inflammation. 16,18,19 Importantly, most of the reported microsatellite analysis has been undertaken on bulk samples of either the tumor or nonmalignant epithelium and, thus, the status of MSI-H could be due to the pooling effect of individual microfoci which showed MSI(-L) in different markers.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9][10][11][12][13][14][15] In lesions undergoing chronic inflammation, microsatellite instability (MSI) is a possible genetic alteration, and high-and low-level of MSI (MSI-H and MSI-L) has been described in UC associated neoplasm (UCAN). [16][17][18][19][20][21][22][23] However, the reported frequency of MSI-H, a consequence of a defective mismatch repair (MMR) system (notably MLH1 or MSH2), and MSI-L, a consequence in part of O 6 -methylguanine-DNA methyltransferase (MGMT) deficiency, 24 has varied considerably from 9 to 50%, and 11 to 85%, respectively. 22,[25][26][27] In situation of considerable genetic heterogeneity within a sample, collection of samples without microdissection could possibly obscure the findings of MSI.…”

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Heterogeneous microsatellite instability observed within epithelium of ulcerative colitis

Ozaki

Nagasaka

Notohara

et al. 2006

Intl Journal of Cancer

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Microsatellite instability (MSI) has been associated with colitic cancer. However, reported frequency of MSI was varied and the association of MSI with mismatch repair (MMR) deficiency was unclear. In addition, the occurrence of genetic alterations in stromal cells within ulcerative colitis (UC) is still controversial. We therefore sampled 164 microareas in various pathological lesions of UC with or without colitic cancer and studied the MSI status in relation to the DNA repair protein expressions. A total of 129 microfoci from colorectal tissue of 5 colitic cancer patients and 35 microfoci of 7 UC patients (without neoplasm) were carefully sampled by laser-capture microdissection. MSI was analyzed in each microsamples. The protein expression of MMR genes (MLH1, MSH2, MSH6), O 6 -methylguanine-DNA methyltransferase and p53 were assessed by immunohistochemical analysis. Variety of di-nulcleotide microsatellite markers was altered in individual microfoci from different morphological epithelial lesions, in full range of nonneoplastic epithelium to colitic cancer. Interestingly, MSI was not observed in stromal cells at any sites, including those within colitic cancer/dysplasia lesions. Expression of the MMR proteins was not lost in any of the lesions examined. Microsatellite alterations rather seem to be related to the initiation than to the progression of colitic cancer. ' 2006 Wiley-Liss, Inc.Key words: colitic cancer; ulcerative colitis; microsatellite instability; stroma; mismatch repair Colorectal epithelium with a long-standing ulcerative colitis (UC) has an increased risk of developing cancer. 1-6 An invasive colitic cancer often arises from a preceding flat dysplastic epithelium and tend to develop multifocally over the background inflamed epithelium, whilst sporadic colorectal cancer (CRC) develops from a preexisting adenoma, suggesting a dissimilar carcinogenic pathway in colitic cancer. [7][8][9][10][11][12][13][14][15] In lesions undergoing chronic inflammation, microsatellite instability (MSI) is a possible genetic alteration, and high-and low-level of MSI (MSI-H and MSI-L) has been described in UC associated neoplasm (UCAN). [16][17][18][19][20][21][22][23] However, the reported frequency of MSI-H, a consequence of a defective mismatch repair (MMR) system (notably MLH1 or MSH2), and MSI-L, a consequence in part of O 6 -methylguanine-DNA methyltransferase (MGMT) deficiency, 24 has varied considerably from 9 to 50%, and 11 to 85%, respectively. 22,[25][26][27] In situation of considerable genetic heterogeneity within a sample, collection of samples without microdissection could possibly obscure the findings of MSI. 28,29 In fact, analysis of mixed MSI-L components could result in a false diagnosis as MSI-H. To verify true MSI status and to clarify the significance of MSI in colitic carcinogenesis, precise analysis of individual microfoci from various pathological lesions (including stroma) is required. 16,18,19 Accordingly, we sampled 164 microfoci, including nondysplastic epithelium, dysplastic epithel...

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Genetic Alterations in Ulcerative Colitis‐associated Neoplasia Focusing on APC, K‐ras Gene and Microsatellite Instability

Cited by 69 publications

References 39 publications

Contrasting molecular pathology of colorectal carcinoma in Egyptian and Western patients

Contrasting molecular pathology of colorectal carcinoma in Egyptian and Western patients

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

Heterogeneous microsatellite instability observed within epithelium of ulcerative colitis

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