Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma
Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma
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DOI：
10.1038/sj.jid.5700026
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发表时间：
2006-01-01
影响因子：
6.5
通讯作者：
Haluska, Frank G.
中科院分区：
文献类型：
--
作者：
Goel, Vikas K.;Lazar, Alexander J. F.;Haluska, Frank G.
V-RAF小鼠肉瘤病毒癌基因同源B(BRAF)是大鼠肉瘤癌基因(RAS)信号通路的下游效应因子，在黑色素瘤和其他肿瘤中被描述为频繁的体细胞突变。我们对黑色素瘤细胞系的分析表明，BRAF的激活突变可以与磷酸酶和张力蛋白同源蛋白(PTEN)的失活同时发生，但神经母细胞瘤RAS(NRAS)的突变并不一致。我们确定了69例原发性皮肤黑色素瘤中BRAF和NRAS基因突变的并存发生率以及PTEN表达的变化。57%的病例出现BRAF突变。17%的样本NRAS发生突变，仅发生在外显子2。2例同时发现BRAF和NRAS突变。免疫组织化学检测显示，19%的肿瘤组织中PTEN蛋白表达缺失或显著降低。7个PTEN降低的肿瘤获得了符合测序的DNA，3个肿瘤在BRAF中也显示了突变，但在NRAS中没有突变。总体而言，在13个PTEN表达降低的肿瘤中，有11个(85%)的肿瘤厚度大于3.5 mm，且Breslow厚度增加与PTEN表达缺失或降低的相关性具有统计学意义(P<；0.0001)。NRAS突变与PTEN表达降低不一致，且NRAS和BRAF同时突变的情况很少见。
Frequent somatic mutation of v-raf murine sarcoma viral oncogene homolog B (BRAF), a downstream effector of the rat sarcoma oncogene (RAS) signaling pathway, is described in melanoma and other tumors. Our analysis of melanoma cell lines suggests that activating mutations in BRAF can occur simultaneously with inactivation of phosphatase and tensin homolog (PTEN), but neuroblastoma RAS (NRAS) mutations are not coincident. We determined the concurrent prevalence of mutations in BRAF and NRAS, and alteration of PTEN expression in 69 primary cutaneous melanomas. BRAF mutations were seen in 57% of cases. NRAS was mutated in 17% of samples, exclusively in exon 2. Two cases showed concurrent BRAF and NRAS mutations. Using immunohistochemistry, PTEN protein expression was lost or greatly reduced in 19% of tumors. Seven tumors with reduced PTEN yielded DNA amenable to sequencing, and three also showed mutation in BRAF but none in NRAS. In all, 11 (85%) of 13 tumors showing reduced PTEN expression were greater than 3.5mm thick, and the association of increasing Breslow thickness and loss or reduction of PTEN expression was statistically significant (P < 0.0001). Mutations in NRAS were not coincident with reduced PTEN expression, and the concurrent mutation of NRAS and BRAF was rare.