title: BRAF gene 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.
authors.affiliation: Institute of Pathology, University of Leipzig, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tannapfel
authors.forename: Susanne
authors.initials: S
authors.lastname: Vomschloss
authors.forename: Dorothee
authors.initials: D
authors.lastname: Karhoff
authors.forename: Anett
authors.initials: A
authors.lastname: Markwarth
authors.forename: Ulrich R
authors.initials: UR
authors.lastname: Hengge
authors.forename: Christian
authors.initials: C
authors.lastname: Wittekind
authors.forename: Rudolf
authors.initials: R
authors.lastname: Arnold
authors.forename: Dieter
authors.initials: D
authors.lastname: Hörsch
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002276:Carcinoid Tumor / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000032:analysis; D004067:Digestive System Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015408:Gastrinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation; D017599:Neuroectodermal Tumors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D003969:Vipoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D017931:DNA Primers; D004273:DNA, Neoplasm; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048052:Mitogen-Activated Protein Kinase 3