Mutational analysis of the BRAF, RAS and EGFR genes in human adrenocortical carcinomas
Mutational analysis of the BRAF, RAS and EGFR genes in human adrenocortical carcinomas
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DOI：
10.1677/erc-08-0101
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发表时间：
2009-06-01
影响因子：
3.9
通讯作者：
Mitsiades, Nicholas
中科院分区：
文献类型：
--
作者：
Kotoula, Vassiliki;Sozopoulos, Elias;Mitsiades, Nicholas
丝氨酸/苏氨酸激酶B-Raf在Ras/Raf/MEK/ERK途径中起关键作用，该途径传递细胞增殖和存活的细胞外信号。表皮生长因子受体（EGFR）是一种介导增殖和存活信号的跨膜酪氨酸激酶（TK）受体，在多种正常和肿瘤组织中表达。EGFR抑制剂在携带激活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缓解。我们通过DNA测序评估了肾上腺癌（35个肿瘤标本和两个细胞系）中BRAF（外显子11和15）、KRAS（外显子1和2）、NRAS（外显子1和2）和EGFR（外显子18-21）突变的存在。BRAF突变在两种癌中发现（5.7%）。四种癌（11.4%）携带EGFR TK结构域突变，一种标本携带KRAS突变，另一种携带两种NRAS突变。BRAF和EGFR突变的肿瘤标本对磷酸化形式的MEK和ERK激酶的免疫染色比其野生型对应物强。EGFR突变型癌与野生型癌相比，EGFR（Tyr 992）磷酸化水平增加。我们的结论是，BRAF，RAS和EGFR突变发生在一个子集的人肾上腺皮质癌。Ras/Raf/MEK/ERK和EGFR通路的抑制剂代表了未来在精心选择的携带各自激活突变的肾上腺皮质癌患者中进行临床试验的候选靶向治疗。
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.