BRAFGene Mutations Are Rare Events in Gastroenteropancreatic Neuroendocrine Tumors

Abstract

The BRAF gene, one of the human isoforms of RAF, is activated by ras, leading to cooperative effects in cells responsive to growth factor signals. We studied the frequency of BRAF and k-ras-2 mutations in primary neuroendocrine gastroenteropancreatic (GEP) tumors. Mutation analysis of the BRAF and k-ras-2 genes was performed in 40 primary neuroendocrine tumors of the GEP system. The expression of extracellular signaling-related kinase (ERK) 1/2, an important downstream point of convergence in the ras-RAF-mitogen-activated protein-ERK pathway was analyzed immunohistochemically. We detected one 1796 T-->A BRAF mutation that led to a substitution of valine by glutamic acid at position 599 (V599E) in 40 primary neuroendocrine GEP tumors (3%). We failed to detect specific mutation of the k-ras-2 gene. We identified constitutively activated ERK in almost all neuroendocrine tumor tissues tested irrespective of BRAF mutation or localization or functional activity. These results suggest that BRAF mutations do not have a role in tumorigenesis of neuroendocrine tumors. Nevertheless, activation of the RAF/mitogen-activated protein kinase pathway might have a causative role in the development of neuroendocrine tumors, independent of BRAF or k-ras-2 mutation.

GNA15 expression in small intestinal neuroendocrine neoplasia: Functional and signalling pathway analyses

“…It should be noted that a decreased phosphorylation in p70S6K/p85S6K, two isoforms of the same kinase belonging to the same signalling pathway [45] and downstream of Akt [46], and considered a marker of Akt signalling was not observed. This suggests the principle effector is through ERK, well-known to be upregulated in SI-NENs [47,48]. A number of GPCRs activate NFκB via Gi-or Gq-dependent pathways and an intricate signalling network exists between GNA15-coupled receptors and the IKB kinase (IKK)/NFkB pathway [49].…”

MSH2 and CXCR4 involvement in malignant VIPoma

“…Only six publications deal with the molecular mechanisms of oncogenesis and metastasis development in VIPoma, reporting no more than two cases in each publication [13-18]. The remaining publication reports on the clinical presentation, diagnostics, and therapeutic options.…”

“…The remaining publication reports on the clinical presentation, diagnostics, and therapeutic options. Amongst others, mutations in the tumor suppression genes DPC4 [15], AIM1 (‘absent in melanoma1’) and PTPRK (receptor type protein-tyrosine phophastase kappa) [14] are shown in metastatic VIPomas while mutations of the proto oncogene BRAF known to play an important role in thyroid cancer and melanoma were not found [15,18]. A series of 35 neuroendocrine tumors of the pancreas showed that defects in DNA mismatch repair are rather rare with the limitation, that no VIPoma case was included [19].…”