Champion KJ, Bunag C, Estep AL, Jones JR, Bolt CH, Rogers RC, Rauen KA, Everman DB. Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome.
BRAF, the protein product of BRAF, is a serine/threonine protein kinase and one of the direct downstream effectors of Ras. Somatic mutations in BRAF occur in numerous human cancers, whereas germline BRAF mutations cause cardio-facio-cutaneous (CFC) syndrome. One recurrent somatic mutation, p.V600E, is frequently found in several tumor types, such as melanoma, papillary thyroid carcinoma, colon cancer, and ovarian cancer. However, a germline mutation affecting codon 600 has never been described. Here, we present a patient with CFC syndrome and a de novo germline mutation involving codon 600 of BRAF, thus providing the first evidence that a pathogenic germline mutation involving this critical codon is not only compatible with development but can also cause the CFC phenotype. In vitro functional analysis shows that this mutation, which replaces a valine with a glycine at codon 600 (p.V600G), leads to increased ERK and ELK phosphorylation compared to wild-type BRAF but is less strongly activating than the cancer-associated p.V600E mutation.
"BRAF. The majority fall into the high-or intermediate-activity class (Rodriguez-Viciana et al. 2006), with only seven also being found in human cancer samples; namely, G469E, F468S, L485F, F595L, V600G, and K601E in CFC patients (Rodriguez-Viciana et al. 2006; Champion et al. 2011), with the intermediateactivity L597V mutation being detected in both NS and CFC patients (Sarkozy et al. 2009; Pierpont et al. 2010). How the same mutations can promote developmental abnormalities when constitutively expressed but cancer when acquired somatically is a critical question to address and is likely related to mechanisms of downstream MEK/ERK pathway activation under different contexts. "
[Show abstract][Hide abstract] ABSTRACT: (L597V)BRAF mutations are acquired somatically in human cancer samples and are frequently coincident with RAS mutations. Germline (L597V)BRAF mutations are also found in several autosomal dominant developmental conditions known as RASopathies, raising the important question of how the same mutation can contribute to both pathologies. Using a conditional knock-in mouse model, we show that endogenous expression of (L597V)Braf leads to approximately twofold elevated Braf kinase activity and weak activation of the Mek/Erk pathway. This is associated with induction of RASopathy hallmarks including cardiac abnormalities and facial dysmorphia but is not sufficient for tumor formation. We combined (L597V)Braf with (G12D)Kras and found that (L597V)Braf modified (G12D)Kras oncogenesis such that fibroblast transformation and lung tumor development were more reminiscent of that driven by the high-activity (V600E)Braf mutant. Mek/Erk activation levels were comparable with those driven by (V600E)Braf in the double-mutant cells, and the gene expression signature was more similar to that induced by (V600E)Braf than (G12D)Kras. However, unlike (V600E)Braf, Mek/Erk pathway activation was mediated by both Craf and Braf, and ATP-competitive RAF inhibitors induced paradoxical Mek/Erk pathway activation. Our data show that weak activation of the Mek/Erk pathway underpins RASopathies, but in cancer, (L597V)Braf epistatically modifies the transforming effects of driver oncogenes.
Genes & development 08/2012; 26(17):1945-58. DOI:10.1101/gad.193458.112 · 10.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Serine/threonine-protein kinase BRAF, a downstream effector of the RAS oncogene along the MEK/ERK signaling pathway, has emerged as an important biological marker for diagnosis, prognosis and therapeutic guidance for human cancers. The high prevalence of BRAF(V600E) activating mutation in papillary thyroid carcinoma, cutaneous malignant melanoma and hairy cell leukemia implies that the mutation is an important 'driver' or 'codriver' in the development of a subset of these cancers. Diagnostically, the BRAF(V600E) mutation is a powerful molecular marker for papillary thyroid carcinoma and, quite possibly, hairy cell leukemia as well. Cancers with a BRAF mutation are generally more aggressive than their counterparts without the mutation. Importantly, mutant BRAF has been a highly attractive target for precision cancer therapy. Indeed, recent studies in the clinical trials of BRAF inhibitors in patients with malignant melanoma are changing the treatment paradigm of this highly lethal disease. BRAF mutation testing using highly sensitive and specific methodology in a molecular diagnostic laboratory is essential in the current clinical practice of oncology.
[Show abstract][Hide abstract] ABSTRACT: BRAF is an oncogene encoding a serine-threonine protein kinase involved in the MAPK signalling cascade. BRAF acts as direct effector of RAS and through the activation of MEK, promotes tumour growth and survival. Approximately, 8% of cancers carry a BRAF mutation. However, the prevalence of this mutation varies significantly across different tumour types. There has been increasing interest in the specific role of BRAF mutations in cancer growth and progression over the last few years, especially since the clinical introduction of therapeutic BRAF inhibitors. In this paper we review the published literature on the role of BRAF mutations in melanoma and colorectal cancer, focusing on similarities and differences of BRAF mutations with respect to frequency, demographics, risk factors, mutation-associated clinico-pathologic and molecular features and clinical implications between these two diseases.
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