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13 germline BRAF variants, 4 of which were silent mutations in coding regions & 9 nucleotide substitutions in introns, were found in melanoma patients and melanoma family, but none appeared statistically likely to be a melanoma susceptibility gene. 13 germline BRAF variants, 4 of which were silent mutations in coding regions & 9 nucleotide substitutions in introns, were found in melanoma patients and melanoma family, but none appeared statistically likely to be a melanoma susceptibility gene. 3 cell lines derived from human choroidal melanoma express B-Raf containing the V599E mutation and showed a 10-fold increase in endogenous B-RafV599E kinase activity and a constitutive activation of the MEK/ERK pathway that is independent of Ras. AKAP9-BRAF fusion was preferentially found in radiation-induced papillary carcinomas developing after a short latency, whereas BRAF point mutations were absent in this group. Although BRAF and NRAS mutations are likely to be important for the initiation and maintenance of some melanomas, other factors might be more significant for proliferation and prognosis in subgroups of aggressive melanoma. Anaplastic thyroid carcinomas which are derived from papillary carcinomas are due to BRAF and p53 mutations. B-Raf and ERK are activated by cyclic AMP after calcium restriction. B-Raf has a role in extracellular signal-regulated kinase (ERK) signaling in T cells and prevents antigen-presenting cell-induced anergy. B-Raf kinase activity regulation by tuberin and Rheb is mammalian target of rapamycin (mTOR)-independent. B-raf is involved in adhesion-independent ERK1/2 signaling in melanocytes. B-raf mutations surrounding Thr439 found in human cancers are unlikely to contribute to increased oncogenic properties of B-raf. BRAF has a role in in squamous cell carcinoma of the head and neck through uncommon mutations. BRAF is occasionally mutated in NHL, and BRAF mutation may contribute to tumor development in some NHLs. BRAF mutation may be acquired during development of metastasis but is not a significant factor for primary melanoma development and disease outcome. BRAF mutation occurs later in thyroid tumor progression and is restricted mainly to papillary thyroid carcinoma and anaplastic thyroid carcinoma. BRAF mutations are associated with conjunctival neoplasms. BRAF mutations are associated with proximal colon tumors with mismatch repair deficiency and MLH1 hypermethylation. BRAF mutations are frequently present in sporadic colorectal cancer with methylated hMLH1. BRAF mutations are rather rare in solitary cold adenomas and adenomatous nodules and do not explain the molecular etiology of ras mutation-negative cold thyroid nodules. BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas. BRAF mutations in colorectal cancers occur only in tumours that do not carry mutations in a RAS gene known as KRAS, and BRAF mutation is linked to the proficiency of these tumours in repairing mismatched bases in DNA. BRAF mutations proved to be absent in tumors from hereditary nonpolyposis colorectal cancer syndrome (HNPCC) families with germline mutations in the MMR genes MLH1 and MSH2. BRAF mutations were seen in stomach neoplasms. BRAF mutations, which are present in a variety of other human cancers, do not seem to be involved in gastric cancer development. BRAF(V599E) is more common genetic alteration found to date in adult sporadic papillary thyroid carcinomas (PTCs). It is unique for this thyroid cancer histotype, and it might drive the development of PTCs of classic papillary subtype. BRAF(V599E) mutation is seven times higher in lesions with structural changes and 13 times higher in growing lesions as compared with lesions without changes. Both BRAF and FBXW7 mutations functionally activate kinase effectors important in pancreatic cancer and extend potential options for therapeutic targeting of kinases in treatment of phenotypically distinct pancreatic adenocarcinoma subsets. Data provide evidence that B-Raf is a positive regulator of T cell receptor-mediated sustained ERK activation, which is required for NFAT activation and the full production of IL-2. Data show that the the RET receptor (RET/PTC), Ras and BRAF function along a linear oncogenic signaling cascade in which RET/PTC induces RAS-dependent BRAF activation and RAS- and BRAF-dependent ERK activation. Data suggest that BRAF T1796A activating mutation is not common in primary uveal melanoma. Data suggest that Rit is involved in a novel pathway of neuronal development and regeneration by coupling specific trophic factor signals to sustained activation of the B-Raf/ERK and p38 MAP kinase cascades. Data suggest that SPRY2, an inhibitor of ERK signaling, may be bypassed in melanoma cells either by down-regulation of its expression in WT BRAF cells, or by the presence of the BRAF mutation. High frequency of BRAF mutations in nevi. High prevalence of BRAF mutations in thyroid cancer is genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. In patients with papillary thyroid cancer, BRAF mutation is associated with poorer clinicopathological outcomes and independently predicts recurrence. In this study, this BRAF mutation was demonstrated in some conjunctival melanoma tissue samples, suggesting that some conjunctival melanomas may share biological features in common with cutaneous melanoma. KSHV-infected cell lines expressed higher levels of B-Raf and VEGF-A; B-Raf-induced VEGF-A expression was demonstrated to be sufficient to enhance tubule formation in endothelial cells. MEK1 interacts with B-Raf. Missense mutation is marker of colonic but not gastric cancer. Mucinous ovarian cancers without a KRAS mutation have not sustained alternative activation of this signaling pathway through mutation of the BRAF oncogene. Mutations are not detectable in plasma cell leukemia and multiple myeloma. Mutations in BRAF gene is associated with malignant melanomas. Mutations in the BRAF protooncogene (V599E)may be an alternative pathway of tumorigenesis of familial colorectal cancer. Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas. Mutations of BRAF or KRAS oncogenes are early events in the serrated polyp neoplasia pathway. CpG island methylation plays a role in serrated polyp progression to colorectal carcinoma. Mutations of the BRAF gene are partly involved in the malignant transformation of the endometrium. Mutations were found in exon 15 in colorectal adenocarcinoma. Mutations within the BRAF gene are useful markers for the differential diagnosis between Spitz nevus and malignant melanoma. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. New enriched PCR-RFLP assay for detecting mutations of BRAF codon 599 mutation in pleural mesotheliomas. None of the cases of gastric cancer showed braf mutations. Our data indicate that BRAF gene mutations are rare to absent events in uveal melanoma of humans. Our findings of a high frequency of BRAF mutations at codon 599 in benign melanocytic lesions of the skin indicate that this mutation is not sufficient by itself for malignant transformation. RAS or BRAF mutations are detected in about 32% of all Barrett's adenocarcinomas; the disruption of the Raf/MEK/ERK (MAPK) kinase pathway is a frequent but also early event in the development of Barrett's adenocarcinoma. REVIEW: our understanding of B-RAF as an oncogene and of its role in cancer. Radiation-induced tumors have a low prevalence of BRAF point mutations and high prevalence of RET/PTC rearrangements. Role of BRAF mutation in facilitating metastasis and progression of papillary thyroid cancer in lymph nodes. Single-cell clones with efficient knockdown of (V 600 E)B-RAF could be propagated in the presence of basic fibroblast growth factor but underwent apoptosis or senescence-like growth arrest upon withdrawal of this growth factor. The BRAF(V599E) mutation appears to be an alternative event to RET/PTC rearrangement rather than to RAS mutations, which are rare in PTC. BRAF(V599E) may represent an alternative pathway to oncogenic MAPK activation in PTCs without RET/PTC activation. The V599E BRAF mutation appears to be a somatic mutation associated with melanoma development and/or progression in a proportion of affected individuals. The data of this study suggest that activating mutations of B-RAF are not a frequent event in gliomas; nevertheless, when present they are associated with high-grade malignant lesions. The estimated proportion of attributable risk of melanoma due to variants in BRAF is 1.6%, but the burden of disease associated with this variant is greater than that associated with the major melanoma locus (CDKN2A) which has a risk of 0.2%. The finding of tandem mutations in thin melanomas makes it more likely that they arise as a simultaneous rather than sequential event. The increasing frequency of BRAF mutations as a function of age could help account for the well documented but poorly understood observation that age is a relevant prognostic indicator for patients with papillary thyroid carcinoma. The lack or low prevalence of BRAF mutation in other thyroid neoplasms is consistent with the notion that other previously defined genetic alterations on the same signaling pathway are sufficient to cause tumorigenesis in most thyroid neoplasms. The results showed that conjunctival nevi, similar to skin nevi, have a high frequency of oncogenic BRAF mutations. These data suggest that MITF is an anti-proliferation factor that is down-regulated by B-RAF signaling and that this is a crucial event for the progression of melanomas that harbor oncogenic B-RAF. These results suggest that BRAF mutations do not have a role in tumorigenesis of neuroendocrine gastroenteropancreatic tumors. These results suggest that the BRAF mutation is unlikely to be involved in gastric carcinogenesis. These studies identify isoprenylcysteine carboxyl methyltransferase as a potential target for reducing the growth of K-Ras- and B-Raf-induced malignancies. Uceal melanomas arise independent of oncogenic BRAF and NRAS mutations. We found mutations in p53, K-ras, and BRAF genes in 35%, 30%, and 4% of tumors, respectively, and observed a minimal or no co-presence of these gene alterations. A novel Ras-independent ERK1/2 activation system in which p110gamma/Raf-1/MEK1/2 and PKA/B-Raf/MEK1/2 cooperate to activate ERK1/2. Activating BRAF mutations may be an important event in the development of papillary thyroid cancer. Activation of this gene may be one of the early events in the pathogenesis of some melanomas. Autoinhibition was negatively regulated by acidic substitutions at phosphorylation sites within the activation loop. CAMP activates ERK and increases proliferation of autosomal dominant polycystic kindey epithelial cells through the sequential phosphorylation of PKA, B-Raf and MAPK in a pathway separate from the classical receptor tyrosine kinase cascade. Copy number gain may represent another mechanism of BRAF activation in thyroid tumors. Determination of mutation specific gene expression profiles in papillary thyroid carcinoma. Gene is mutated in skin melanoma, but not in uveal melanomas. In contrast to cutaneous melanoma, BRAF does not appear to be involved in the pathogenesis of uveal melanoma. Mucosal melanomas of the head and neck do not frequently harbor an activating mutation of BRAF. Mutated in childhood acute lymphoblastic leukemia. Mutated in papillary thyroid cancer. Mutation of BRAF gene could be a potentially useful marker of prognosis of patients with advanced thyroid cancers. Mutations in the BRAF gene and to some extent in the N-ras gene represent early somatic events that occur in melanocytic nevi. Ovarian serous cystadenomas do not contain mutations in either BRAF or KRAS genes. Possible cooperation between BRAF activation and PTEN loss in melanoma development. Results demonstrate that the mutational status of BRAF and KRAS is distinctly different among histologic types of ovarian serous carcinoma, occurring most frequently in invasive micropapillary serous carcinomas and its precursors, serous borderline tumors. Somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. Sustained BRAF(V600E) expression in human melanocytes induces cell cycle arrest, which is accompanied by the induction of both p16(INK4a) and senescence-associated acidic beta-galactosidase (SA-beta-Gal) activity, a commonly used senescence marker. We found 19 cases (38%) to harbor somatic B-raf exon 15 mutations.
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