Kotoula Vassiliki, Sozopoulos Elias, Litsiou Helen, Fanourakis Galinos, Koletsa Triantafyllia, Voutsinas Gerassimos, Tseleni-Balafouta Sophia, Mitsiades Constantine S, Wellmann Axel, Mitsiades Nicholas
Department of Pathology, School of Medicine, Aristotle University of Thessaloniki, University Campus, Thessaloniki 54006, Greece.
Endocr Relat Cancer. 2009 Jun;16(2):565-72. doi: 10.1677/ERC-08-0101. Epub 2009 Feb 3.
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.
丝氨酸/苏氨酸激酶B-Raf在Ras/Raf/MEK/ERK信号通路中起关键作用，该通路传递细胞外信号以促进细胞增殖和存活。几种类型的人类恶性肿瘤存在BRAF激活突变，最常见的是V600E替代突变。表皮生长因子受体（EGFR）是一种跨膜酪氨酸激酶（TK）受体，介导增殖和存活信号，在多种正常组织和肿瘤组织中均有表达。EGFR抑制剂已在携带激活型EGFR TK结构域体细胞突变的非小细胞肺癌患者中产生了客观反应。我们通过DNA测序评估了肾上腺皮质癌（35个肿瘤标本和2个细胞系）中BRAF（第11和15外显子）、KRAS（第1和2外显子）、NRAS（第1和2外显子）和EGFR（第18-21外显子）的突变情况。在2例癌组织（5.7%）中发现了BRAF突变。4例癌组织（11.4%）携带EGFR TK结构域突变。1个标本携带KRAS突变，另1个标本携带2个NRAS突变。在2个肾上腺皮质细胞系中未发现突变。BRAF和EGFR突变的肿瘤标本相较于野生型标本，MEK和ERK激酶磷酸化形式的免疫染色更强。与野生型癌相比，EGFR突变癌的EGFR（Tyr 992）磷酸化增加。我们得出结论，BRAF、RAS和EGFR突变存在于一部分人类肾上腺皮质癌中。Ras/Raf/MEK/ERK和EGFR信号通路抑制剂代表了未来针对精心挑选的携带相应激活突变的肾上腺皮质癌患者进行临床试验的候选靶向治疗药物。
