Comparative analysis of histology, DNA content,p53 and Ki-ras mutations in colectomy specimens with long-standing ulcerative colitis

Holzmann, Karlheinz; Klump, Bodo; Borchard, F; Hsieh, Chih-Jen; Kühn, Alexander; Gaco, Vera; Gregor, Michael; Porschen, Rainer

doi:10.1002/(sici)1097-0215(19980330)76:1<1::aid-ijc1>3.0.co;2-4

Cited by 94 publications

(78 citation statements)

References 18 publications

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“…KRAS mutations were studied in UC-related neoplasia by a number of authors, all suggesting concordantly that the frequency of KRAS mutations is lower in UC-related than in sporadic colorectal cancer. [25][26][27][28] We can corroborate these data with a frequency of 18% for KRAS mutations in UC-related cancers, which is in keeping with the frequencies found by others. 25,26 The expression level of activated MAPK protein in UC-related cancers was higher than in corresponding nondysplastic UC mucosa but was independent of the mutation status of the KRAS and BRAF genes.…”

Section: Discussionsupporting

confidence: 89%

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Mutations of the BRAF gene in ulcerative colitis‐related colorectal carcinoma

Aust

Haase

Dobryden

et al. 2005

Intl Journal of Cancer

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The Raf/MEK/ERK (MAPK) signal transduction cascade is an important mediator of a number of cellular fates including growth, proliferation and survival. The BRAF gene is activated by oncogenic Ras, leading to cooperative effects in cells responding to growth factor signals. Our study was performed to elucidate a possible function of BRAF in ulcerative colitis (UC)-related colorectal carcinogenesis. Mutations of BRAF and KRAS were determined in 33 UC-related colorectal cancers by direct DNA sequencing analyses after microdissection. Mismatch-repair deficiency was assessed by immunohistochemistry for major mismatch-repair proteins hMLH1, hMSH2 and hMSH6 and microsatellite analyses of the BAT25 and BAT26 loci. Hypermethylation of the hMLH1 promoter was also tested. The results obtained were correlated with histopathologic variables. Activating BRAF missense mutations were identified in 3/33 UC-related cancers (9%), 2 of which exhibited a loss of hMLH1-protein expression and hypermethylation of the hMLH1 promoter. Corresponding nondysplastic UC-mucosa of these patients did not show BRAF mutations. KRAS mutations were found in 6/33 (18%) UC cancers. All 6 UC cancers with KRAS mutations had an intact BRAF gene as the 3 cancers with BRAF mutations had an intact KRAS gene. There was no significant correlation between BRAF or KRAS status and clinicopathologic variables. Our data indicate that BRAF mutations are not an initiating event in UC-related carcinogenesis and are associated with mismatch-repair deficiency through hMLH1-promoter hypermethylation. Disruption of the Raf/MEK/ERK (MAPK) kinase pathway-either through RAS or BRAF mutation-was detected in 27% of all UC-related cancers and thus plays an important role in UC-related carcinogenesis. ' 2005 Wiley-Liss, Inc.Key words: ulcerative colitis; colorectal cancer; BRAF; KRAS; histopathology Patients with longstanding ulcerative colitis have an increased risk of developing colorectal cancer compared to an age-matched control group. The risk of developing colorectal neoplasia increases with the duration and the extent of disease.1,2 Like sporadic colorectal cancer, 3 UC-related cancer is thought to evolve through a multistep process of increasing genomic instability, accumulation of mutations and clonal expansion. Although UC-related and sporadic colorectal cancers share a common set of genomic alterations, UC-related carcinogenesis appears to differ from sporadic colorectal carcinogenesis by different frequencies of specific aberrations and by different times of onset of these alterations. 4,5 Since the discovery of the role of RAS oncogenes in tumorigenesis, we have witnessed an explosion of research in the signal transduction area.6,7 A key RAS effector pathway involves the kinase cascade RAF/MEK/ERK. In the quest to understand how RAS transmits extracellular growth signals, the MAP kinase (MAPK) pathway has emerged as an important route between membranebound RAS and the nucleus. [8][9][10] Signalling through the MAPK cascade is transduced by GTP loading of RAS leadi...

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Section: Discussionsupporting

confidence: 89%

“…There is concordance in that the frequency of KRAS mutations is lower in UC-related than in sporadic colorectal cancer. [25][26][27][28] In our study, we analysed the status of the BRAF gene together with KRAS to elucidate a possible role of these genes in UC-related neoplasia. …”

mentioning

confidence: 99%

Mutations of the BRAF gene in ulcerative colitis‐related colorectal carcinoma

Aust

Haase

Dobryden

et al. 2005

Intl Journal of Cancer

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“…12,13,[16][17][18] UCAN has a low incidence of K-ras mutations, 19,20) but there are some reports of a relatively high incidence of Kras mutations among sporadic carcinomas. 13,14,21,22) However, there is still little information about the genetic alterations in UCAN and no clear conclusion has been reached. Therefore, we investigated MSI, which is found in a certain fraction of colorectal carcinomas, 23,24) and the state of APC and K-ras genes, in which mutations occur in the early stage of sporadic colorectal tumorigenesis.…”

mentioning

confidence: 99%

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

Umetani

Sasaki

Watanabe

et al. 1999

Japanese Journal of Cancer Research

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The status of genetic alterations in ulcerative colitis (UC)-associated neoplasia (UCAN) was investigated focusing on microsatellite instability (MSI) which is seen in a certain fraction of colorectal carcinomas, and adenomatous polyposis coli (APC) gene and K-ras gene, in which mutations occur in the early stage of sporadic colorectal tumorigenesis. Thirty-one UCAN from 15 UC patients who had undergone colorectal resection at our institution were investigated. There were 8 lesions of invasive carcinoma, 15 high-grade dysplasia (HGD) and 8 low-grade dysplasia (LGD). DNA was extracted from each neoplastic lesion and corresponding non-neoplastic tissue by a microdissection method. MSI status at 9 microsatellite loci, loss of heterozygosity (LOH) at the APC locus, and Kras codon 12 point mutation were examined. As for MSI, 4/31 (13%) UCAN (carcinoma: 1/8 (13%), HGD: 2/15 (13%), LGD: 1/8 (13%)) were MSI-high (3 or more unstable loci) and 12/31 (39%) UCAN (carcinoma: 3/8 (38%), HGD: 6/15 (40%), LGD: 3/8 (38%)) were MSI-low (1 or 2 unstable loci). LOH at the APC locus was not found in 9 UCAN from 6 informative (heterozygous) cases. The K-ras mutation rate of UCAN was 3/31 (9.7%) (carcinoma: 2/8 (25%), HGD: 1/15 (7%) and LGD: 0/8). MSI is relatively common in UCAN and is present at the early stage of tumorigenesis of UCAN, while the involvement of genetic alterations of the APC gene and K-ras gene is small. MSI may be one of the mechanisms of the increased neoplastic risk in UC, and UCAN may develop through a different carcinogenic pathway from sporadic carcinomas.

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“…Hereby, flow and/or image cytometry might serve as reliable tools with excellent clinical applicability also for high-throughput clinical diagnostics. Interestingly, reported frequencies of aneuploidy in UCCs vary inconsistently between 28.6% and 100% (Holzmann et al 1998;Fozard et al 1986). This rather astonishing range could be due to different ploidy assessment techniques, e.g., flow cytometry versus image cytometry, different standardization methodologies, as well as varying definitions of the terms "diploidy" and "aneuploidy" (Holzmann et al 1998;Fozard et al 1986;Klump et al 1997;Clausen et al 2001;Levine et al 1991).…”

Section: Nuclear Aneuploidy and Prognosis In Sporadic And Uc-associatmentioning

confidence: 99%

“…Interestingly, reported frequencies of aneuploidy in UCCs vary inconsistently between 28.6% and 100% (Holzmann et al 1998;Fozard et al 1986). This rather astonishing range could be due to different ploidy assessment techniques, e.g., flow cytometry versus image cytometry, different standardization methodologies, as well as varying definitions of the terms "diploidy" and "aneuploidy" (Holzmann et al 1998;Fozard et al 1986;Klump et al 1997;Clausen et al 2001;Levine et al 1991). In addition, a major drawback of the above mentioned studies might be the overall low number of UCC cases analyzed, varying from single case studies up to 17 individual UCC patients (Clausen et al 2001;Makiyama et al 1995;Burmer, Rabinovitch, and Loeb 1991).…”

Section: Nuclear Aneuploidy and Prognosis In Sporadic And Uc-associatmentioning

confidence: 99%

Ulcerative Colitis and Colorectal Cancer: Aneuploidy and Implications for Improved Screening

Habermann¹,

Auer²,

Ried³

et al. 2012

Ulcerative Colitis From Genetics to Complications

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Comparative analysis of histology, DNA content,p53 and Ki-ras mutations in colectomy specimens with long-standing ulcerative colitis

Cited by 94 publications

References 18 publications

Mutations of the BRAF gene in ulcerative colitis‐related colorectal carcinoma

Mutations of the BRAF gene in ulcerative colitis‐related colorectal carcinoma

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

Ulcerative Colitis and Colorectal Cancer: Aneuploidy and Implications for Improved Screening

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