Dear Sir,
The RAS proteins participate in the RAS-RAF-MEK-ERK-MAPKinase pathway, which mediates cellular responses to growth signals. 1 There are 3 RAF genes, each encoding cytoplasmic serine/threonine kinases that are regulated by binding to RAS. 1,2 We have recently reported that BRAF is somatically mutated in a number of human cancers, including malignant melanoma, colorectal carcinoma and ovarian borderline (low malignant potential) tumors. 3 Mutations in BRAF occur in 2 regions of the BRAF kinase domain, the G loop (which mediates binding of ATP) and the activation segment (which protects the substrate binding site). Mutated forms of BRAF that have been studied so far have elevated kinase activity and can transform NIH3T3 cells. 3 More recently, we have also documented that there are many similarities in the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia, 4 suggesting that BRAF mutations may be biologically equivalent to KRAS mutations in colorectal cancer development. In support of this notion, the BRAF and KRAS mutations exhibit a trend toward mutual exclusion in human tumors. [3][4][5] Interestingly Rajagopalan et al. have observed a higher incidence of BRAF mutation in colorectal cancer with microsatellite instability (MSI) compared to the microsatellite stable (MSS) counterpart, 5 although similar relationships were not documented in our series.
Gastric cancer are well known, sharing many phenotypic and molecular genetic changes with colorectal cancer. In particular, the intestinal type of gastric cancer is believed to have gone through the process of chronic gastritis, intestinal metaplasia, dysplasia followed by malignant transformation, the latter steps being analogous to the adenoma-carcinoma sequence in colorectal cancer. Somatic mutation of the RAS genes, in particular KRAS, is common in colorectal cancer, being found in more than one-third of cases. 6,7 Unexpectedly, recent molecular studies in gastric cancers have mostly found a low incidence of KRAS mutation, in the range of 7-20%. 8 -10 Similar to colorectal cancer, gastric cancers have been reported to show highlevel microsatellite instability due to mismatch repair defects in 10 -20% cases. [11][12][13] We therefore assessed the presence of BRAF and KRAS mutations in 94 gastric cancers and their relationship to mismatch repair status. Frozen tumors and normal gastric mucosa were collected from gastrectomy specimens in Queen Mary Hospital, The University of Hong Kong. Fifty-four were from male and 40 from female patients. The patients' age ranged from 35-88 years (mean age 68 years). Seventy were located in the antrum, 15 were located in the body, 8 were located in the cardia and 1 diffusely involving the whole stomach. Seventy were of the intestinal type and 15 were Grant sponsor: Research Grants Council of the Hong Kong Special Administrative Region; Grant numbers: HKU 7330/00M, HKU7006/99M.