Mutational analysis of the BRAF, RAS and EGFR genes in human adrenocortical carcinomas.
Title | Mutational analysis of the BRAF, RAS and EGFR genes in human adrenocortical carcinomas. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Kotoula, V., Sozopoulos E., Litsiou H., Fanourakis G., Koletsa T., Voutsinas G., Tseleni-Balafouta S., Mitsiades C. S., Wellmann A., & Mitsiades N. |
Journal | Endocr Relat Cancer |
Volume | 16 |
Issue | 2 |
Pagination | 565-72 |
Date Published | 2009 Jun |
ISSN | 1351-0088 |
Keywords | Adolescent, Adrenocortical Carcinoma, Adult, Aged, Aged, 80 and over, Child, Female, Genes, ras, Humans, Immunoenzyme Techniques, Male, Middle Aged, Mutation, Phosphorylation, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, ras Proteins, Receptor, Epidermal Growth Factor, Retrospective Studies, Young Adult |
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. |
DOI | 10.1677/ERC-08-0101 |
Alternate Journal | Endocr. Relat. Cancer |
PubMed ID | 19190079 |