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This Article Full Text Full Text (PDF) All Versions of this Article: ERC-08-0101v1 16/2/565    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kotoula, V. Articles by Mitsiades, N. PubMed PubMed Citation Articles by Kotoula, V. Articles by Mitsiades, N.

Department of Pathology, School of Medicine, Aristotle University of Thessaloniki, University Campus, Thessaloniki 54006, Greece
¹ Department of Pathology, University of Athens, Athens, Greece
² Laboratory of Environmental Mutagenesis and Carcinogenesis, Institute of Biology, NCSR ‘Demokritos’, GR-15310 Athens, Greece
³ Department of Medical Oncology, Harvard Medical School, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
⁴ Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
⁵ Institute of Pathology, University Clinic, RWTH Aachen, 52074 Aachen, Germany
⁶ Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

(Correspondence should be addressed to N Mitsiades; Email: mitsiadn{at}mskcc.org; V Kotoula; Email: vkotoula{at}auth.gr)

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.