Mutational analysis of the BRAF, RAS and EGFR genes in human adrenocortical carcinomas Journal Article


Authors: Kotoula, V.; Sozopoulos, E.; Litsiou, H.; Fanourakis, G.; Koletsa, T.; Voutsinas, G.; Tseleni-Balafouta, S.; Mitsiades, C. S.; Wellmann, A.; Mitsiades, N.
Article 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. © 2009 Society for Endocrinology.
Keywords: immunohistochemistry; mitogen activated protein kinase; adolescent; adult; child; controlled study; human tissue; protein phosphorylation; school child; aged; aged, 80 and over; middle aged; retrospective studies; young adult; unclassified drug; oncoprotein; human cell; exon; genetics; mutation; proto-oncogene proteins; protein domain; metabolism; epidermal growth factor receptor; receptor, epidermal growth factor; cancer cell culture; pathology; mutational analysis; phosphorylation; retrospective study; wild type; adrenal cortex carcinoma; enzyme immunoassay; immunoenzyme techniques; dna sequence; ras protein; ras proteins; genes, ras; b raf kinase; oncogene ras; mitogen activated protein kinase kinase; proto-oncogene proteins b-raf; epidermal growth factor receptor kinase; n ras protein; braf protein, human; egfr protein, human; kras protein, human; adrenal cortex cell; gene location; adrenocortical carcinoma
Journal Title: Endocrine-Related Cancer
Volume: 16
Issue: 2
ISSN: 1351-0088
Publisher: Bioscientifica Ltd  
Date Published: 2009-06-01
Start Page: 565
End Page: 572
Language: English
DOI: 10.1677/erc-08-0101
PUBMED: 19190079
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 3" - "Export Date: 30 November 2010" - "CODEN: ERCAE" - "Source: Scopus"
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