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

Abstract

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...

British Society of Gastroenterology position statement on serrated polyps in the colon and rectum

“…Serrated neoplasia accounted for 28.9% (11 out of 38) of the non-invasive dysplastic lesions abutting IBD carcinomas but only 3.4% (1 out of 29) of control specimens. Aust et al 159 demonstrated activating BRAF mutations typical of SSPs were identified in 9% (3 out of 33) of colitis-associated cancers, consistent with the hypothesis that some colitis-associated cancers may arise through the serrated pathway.…”

Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia

“…Based on the previous reports, frequency of BRAF mutations is less in sporadic CRCs (6–11%) and in UC-associated colorectal neoplasia (9%) (Aust et al , 2005). It is reported that BRAF mutations frequency is higher in microsatellite instable CRCs developed through the mutator or serrated pathway (Aust et al , 2005). Frequent somatic mutations in TGFBR2 and SMAD4 , members of canonical TGF-β signalling pathway, were reported in CRCs.…”

Tumour budding in colorectal carcinoma

“…These tumours are traditionally separated from the rest on clinical grounds. Though APC gene mutations and K‐ras gene mutations seem to be less frequent, the molecular pathology as unravelled so far does not allow a clear distinction of these from sporadic colorectal carcinoma 45,46 . If indeed similar pathways are operative, tumour budding in ulcerative colitis‐related colorectal carcinomas may be expected to be similar to sporadic colorectal carcinomas.…”