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V Kotoula, Department of Pathology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54006, Greece, Thessaloniki, Greece
E Sozopoulos, Department of Pathology, University of Athens, Athens, Greece, Athens, Greece
H Litsiou, Dept. of Pathology, University of Athens, athens, Greece
G Fanourakis, Dept. of Pathology, University of Athens, athens, Greece
T Koletsa, Dept of Pathology, Aristotle University of Thessaloniki, Thessaloniki, Greece
G Voutsinas, Lab of environmental mutagenesis & carcinogenesis, Institute of Biology, NCSR, Demokritos, athens, Greece
S Tseleni-Balafouta, Pathology, University of Athens, Athens, Greece
C Mitsiades, Dana Farber Cancer Institute, Harvard Medical School, Boston, United States
A Wellmann, Institute of Pathology, University Clinic, RWTH Aachen, 52074 Aachen, Germany, Aachen, Germany
N Mitsiades, DFCI, Boston, United States

Correspondence: Nicholas Mitsiades, Email: nmitsiades{at}partners.org

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 2 cell lines) by DNA sequencing. BRAF mutations were found in 2 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 2 adrenocortical cell lines. BRAF- and EGFR-mutant tumor specimens exhibited stronger immunostaining for the phosphorylated forms of the MEK and ERK kinases that their wild-type counterparts. EGFR-mutant carcinomas exhibited increased phosphorylation of EGFR (Tyr 992) compared to 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.