Mutations of BRAF and KRAS2 in the development of Barrett's adenocarcinoma

Abstract

Activation of the Raf/MEK/ERK (MAPK) signal transduction cascade by RAS mutations has been found in a variety of human cancers. Mutations of BRAF provide an alternative route for activation of this signalling pathway. To determine the role of mutations in BRAF and KRAS2 in the neoplastic progression of Barrett's adenocarcinoma, we analysed both genes for common mutations. After microdissection, DNA of 19 Barrett's adenocarcinomas, 56 Barrett's intraepithelial neoplasias (n ¼ 29 low-grade intraepithelial neoplasia (LGIN) and n ¼ 27 high-grade intraepithelial neoplasia (HGIN)), 30 Barrett's mucosa without neoplasia and normal squamous, as well as gastric epithelium, were analysed for BRAF and KRAS2 mutation. Activating BRAF mutations were identified in 2/19 Barrett's adenocarcinomas (11%) and in 1/27 HGIN (4%). KRAS2 mutations were found in four out of 19 (21%) Barrett's adenocarcinomas examined and in three cases of HGIN (11%). In LGIN as well as in normal gastric or oesophageal mucosa, neither BRAF nor KRAS2 mutations were detected. All lesions with KRAS2 mutations had an intact BRAF gene. The status of mismatch-repair proteins was neither related to BRAF nor KRAS2 mutations. These data indicate that RAS or BRAF mutations are detected in about 32% of all Barrett's adenocarcinomas. We conclude that the disruption of the Raf/MEK/ERK (MAPK) kinase pathway is a frequent but also early event in the development of Barrett's adenocarcinoma.

Sensitive and Specific KRAS Somatic Mutation Analysis on Whole-Genome Amplified DNA from Archival Tissues

“…To minimize the chance of PCR amplicon contamination pre-and post-PCR rooms were strictly separated, and we used a direct PCR to avoid pseudogene amplification rather than nested PCR for KRAS mutation detection. 37,38 Another factor to consider is tumor heterogeneity. In samples with lower tumor percentage and low amount of the mutated allele, automated Sanger sequence analysis could miss variants, whereas HRM could still detect mutations in gDNA and wgaDNA from samples with low tumor percentages.…”

Concepts in the Prevention of Adenocarcinoma of the Distal Esophagus and Proximal Stomach

“…58 Recently, studies have demonstrated K-ras mutations in 11% to 40% of esophageal adenocarcinomas, but few data are available on the frequency of Ras mutations in gastric cardia adenocarcinomas. 57,59 Moreover, available data do not support an important role for oncogenic B-raf in adenocarcinomas of the upper gastrointestinal tract. 57,60,61 Given the pivotal role of Ras proteins in the regulation of cell growth, it is not surprising that inhibitors of Ras are in development as anticancer therapies.…”

“…57,59 Moreover, available data do not support an important role for oncogenic B-raf in adenocarcinomas of the upper gastrointestinal tract. 57,60,61 Given the pivotal role of Ras proteins in the regulation of cell growth, it is not surprising that inhibitors of Ras are in development as anticancer therapies. The enzyme farnesyltransferase (FTase) catalyzes the addition of a farnesyl isoprenoid moiety to Ras, a modification which allows Ras to attach to the inner surface of the plasma membrane and trigger cell signaling.…”

“…56,57 Ras proteins play central roles in the regulation of normal cell growth. In response to a variety of growth factors and cytokines, Ras proteins initiate a number of downstream signaling pathways that regulate progression through the cell cycle and thus cell proliferation.…”

Loss of heterozygosity of Kras2 gene on 12p12-13 in Chinese colon carcinoma patients

“…Clinical and experimental studies have shown that point mutation of Kras2 gene plays an important role in the development and progression of tumors [1][2][3][4] . However, it has been reported that wild type Kras2 gene has inhibitory effects on tumor growth and proliferation [5] .…”