Microsatellite instability and K- mutations in patients with ulcerative colitis

Lyda, Mark H.; Noffsinger, Amy; Belli, Jenine; Fenoglio‐Preiser, Cecilia M.

doi:10.1053/hupa.2000.7643

Cited by 52 publications

(24 citation statements)

References 28 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: 90%

“…[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. This may be due to other alterations within the RAS/RAF/MAPK pathway, like activation of upstream tyrosine kinases or G-protein-coupled receptors, or due to parallel pathways involved in UC-related carcinogenesis that contribute to an increased activated MAPK protein expression.…”

Section: Discussionsupporting

confidence: 90%

“…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. …”

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confidence: 99%

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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: 90%

Section: Discussionsupporting

confidence: 90%

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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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“…Braakhuis et al (2003) expanded this theory and proposed that the field was actually a clonally expanded area of mutated cells. Clonally expanded mutated patches have been documented previously in dysplastic and phenotypically normal mucosa of colitis patients (Lyda et al 1998(Lyda et al , 2000. Leedham et al (2009) identified field cancerisation in one interesting patient when they demonstrated that three leftsided tumours and some of the intervening chronically inflamed but phenotypically non-dysplastic mucosa shared the same founder mutation, suggesting widespread clonal expansion of a progenitor clone from which the three spatially independent tumours arose.…”

Section: Field Cancerisationmentioning

confidence: 70%

Inflammatory Bowel Disease and Colon Cancer

Jawad

Direkze

Leedham

2011

Recent Results in Cancer Research

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The inflammatory bowel diseases (IBD); Crohn's and Ulcerative colitis, result from an altered host response to intestinal flora. Recurrent inflammation with ulceration and tissue restitution confers an increased risk of cancer in both UC and Crohns, and genome wide searches have identified a number of disease susceptibility alleles. The carcinogenesis pathway in colitis-associated colorectal cancer (CACRC) is less clearly understood than it's sporadic counterpart. Clonal ordering experiments have indicated the order and timing of chromosomal instability and common genetic mutations. Epigenetic changes such as DNA methylation and histone modification are thought to play an increasingly important role in inflammation induced carcinogenesis. Clonal expansion of procarcinogenic mutations can lead to large fields of mutant tissue from which colitis associated cancers can arise (field cancerisation). Endoscopic screening is the mainstay of surveillance in high-risk patients although the development of appropriate, clinically applicable biomarkers remains a research priority. Despite the expanding field of biological therapy in inflammatory bowel disease the ASA compounds remain the best-studied and most efficacious chemopreventive agents. Colitis associated CRC appears to have a different aetiology, carcinogenesis pathway and clinical course to its sporadic counterpart. Further research including long-term follow up of patient cohorts taking biological therapies will improve the detection and treatment of these important, inflammation-induced malignancies.

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“…The theory was further expanded by Braakhuis et al (Braakhuis et al, 2003), who proposed that the field was in fact a clonally-expanded area of mutated cells. Clonally-expanded mutated patches have been noted in dysplastic (Lyda et al, 1998(Lyda et al, , 2000 and phenotypically normal mucosa of colitis patients (Chaubert et al, 1994). Using individual crypt genetic analysis Leedham et al (Leedham et al, 2009) were able to demonstrate the presence of oncogenic mutations in non-dysplastic crypts surrounding clonal neoplastic lesions, suggesting that the tumours had arisen from a field of genetically mutant yet non-dysplastic crypts.…”

Section: Clonal Expansion and Field Cancerisationmentioning

confidence: 99%