title: Mutational analysis of the BRAF, RAS and EGFR genes in human adrenocortical carcinomas.
abstract: The serine/threonine kinase B-Raf plays a key role in the Ras/Raf/MEK/ERK pathway that relays extracellular signals for cell proliferation and survival. Several types of human malignancies harbor activating BRAF mutations, most frequently a V600E substitution. The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase (TK) receptor that mediates proliferation and survival signaling, is expressed in a wide variety of normal and neoplastic tissues. EGFR inhibitors have produced objective responses in patients with non-small cell lung carcinomas harboring activating EGFR TK domain somatic mutations. We evaluated the presence of mutations in BRAF (exons 11 and 15), KRAS (exons 1 and 2), NRAS (exons 1 and 2), and EGFR (exons 18-21) in adrenal carcinomas (35 tumor specimens and two cell lines) by DNA sequencing. BRAF mutations were found in two carcinomas (5.7%). Four carcinomas (11.4%) carried EGFR TK domain mutations. One specimen carried a KRAS mutation, and another carried two NRAS mutations. No mutations were found in the two adrenocortical cell lines. BRAF- and EGFR-mutant tumor specimens exhibited stronger immunostaining for the phosphorylated forms of the MEK and ERK kinases than their wild-type counterparts. EGFR-mutant carcinomas exhibited increased phosphorylation of EGFR (Tyr 992) compared with wild-type carcinomas. We conclude that BRAF, RAS, and EGFR mutations occur in a subset of human adrenocortical carcinomas. Inhibitors of the Ras/Raf/MEK/ERK and EGFR pathways represent candidate targeted therapies for future clinical trials in carefully selected patients with adrenocortical carcinomas harboring respective activating mutations.
authors.affiliation: Department of Pathology, School of Medicine, Aristotle University of Thessaloniki, University Campus, Thessaloniki 54006, Greece. vkotoula@auth.gr
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kotoula
authors.forename: Elias
authors.initials: E
authors.lastname: Sozopoulos
authors.forename: Helen
authors.initials: H
authors.lastname: Litsiou
authors.forename: Galinos
authors.initials: G
authors.lastname: Fanourakis
authors.forename: Triantafyllia
authors.initials: T
authors.lastname: Koletsa
authors.forename: Gerassimos
authors.initials: G
authors.lastname: Voutsinas
authors.forename: Sophia
authors.initials: S
authors.lastname: Tseleni-Balafouta
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: Axel
authors.initials: A
authors.lastname: Wellmann
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
mesh_terms: D000293:Adolescent; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins