Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia
Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia
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DOI：
10.1158/0008-5472.can-04-1923
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发表时间：
2004-12-15
期刊：
影响因子：
11.2
通讯作者：
Neel, BG
中科院分区：
文献类型：
--
作者：
Bentires-Alj, M;Paez, JG;Neel, BG
含有SH2结构域的蛋白酪氨酸磷酸酶PTPN11 （Shp2）是正常发育所必需的，是生长因子、细胞因子和细胞外基质启动的信号通路的重要组成部分。在许多这些通路中，Shp2作用于Ras的上游。约50%的努南综合征患者有种系PTPN11功能突变。Noonan综合征与某些恶性肿瘤（特别是白血病和神经母细胞瘤）风险增加之间存在关联，最近的数据表明，PTPN11体细胞突变发生在散发性少年髓单细胞白血病、骨髓增生异常综合征、b细胞急性淋巴细胞白血病和急性髓性白血病（AML）的儿童中。没有PTPN11突变的青少年髓细胞白血病患者要么有NF-1纯合子缺失，要么有RAS激活突变。考虑到Shp2在Ras激活中的作用以及Ras在人类肿瘤中的频繁突变，这些数据提出了PTPN11突变在癌症中发挥更广泛作用的可能性。我们询问PTPN11突变是否发生在其他恶性肿瘤中，其中激活RAS突变发生的频率低但显著。对来自13种不同人类肿瘤（包括乳腺、肺、胃和神经母细胞瘤肿瘤以及成人AML和急性淋巴细胞白血病）的PTPN11进行测序，发现了11个错义突变。其中5个已知的突变预测会导致Shp2的激活形式，而6个是新的突变。生化分析证实，一些新的突变导致Shp2活性增加。我们的数据表明，PTPN11的突变在几种人类癌症中以低频率发生，特别是神经母细胞瘤和AML，这表明Shp2可能是抗肿瘤治疗的新靶点。
The SH2 domain-containing protein-tyrosine phosphatase PTPN11 (Shp2) is required for normal development and is an essential component of signaling pathways initiated by growth factors, cytokines, and extracellular matrix. In many of these pathways, Shp2 acts upstream of Ras. About 50% of patients with Noonan syndrome have germ-line PTPN11 gain of function mutations. Associations between Noonan syndrome and an increased risk of some malignancies, notably leukemia and neuroblastoma, have been reported, and recent data indicate that somatic PTPN11 mutations occur in children with sporadic juvenile myelomonocytic leukemia, myelodysplasic syndrome, B-cell acute lymphoblastic leukemia, and acute myelogenous leukemia (AML). Juvenile myelomonocytic leukemia patients without PTPN11 mutations have either homozygotic NF-1 deletion or activating RAS mutations. Given the role of Shp2 in Ras activation and the frequent mutation of RAS in human tumors, these data raise the possibility that PTPN11 mutations play a broader role in cancer. We asked whether PTPN11 mutations occur in other malignancies in which activating RAS mutations occur at low but significant frequency. Sequencing of PTPN11 from 13 different human neoplasms including breast, lung, gastric, and neuroblastoma tumors and adult AML and acute lymphoblastic leukemia revealed 11 missense mutations. Five are known mutations predicted to result in an activated form of Shp2, whereas six are new mutations. Biochemical analysis confirmed that several of the new mutations result in increased Shp2 activity. Our data demonstrate that mutations in PTPN11 occur at low frequency in several human cancers, especially neuroblastoma and AML, and suggest that Shp2 may be a novel target for antineoplastic therapy.