Mutations of the PTPN11 and RAS genes in rhabdomyosarcoma and pediatric hematological malignancies
Mutations of the PTPN11 and RAS genes in rhabdomyosarcoma and pediatric hematological malignancies
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DOI：
10.1002/gcc.20322
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发表时间：
2006-06-01
影响因子：
3.7
通讯作者：
Hayashi, Y
中科院分区：
文献类型：
--
作者：
Chen, YY;Takita, J;Hayashi, Y
PTPN 11基因是努南综合征（Noonan syndrome，NS）的致病基因，约50%的NS病例与PTPN 11基因有关。鉴于NS与某些恶性肿瘤（特别是白血病和可能的某些实体瘤，包括神经母细胞瘤（NB）和横纹肌肉瘤（RMS））风险增加之间的相关性，最近的研究报告称，PTPN 11中的功能获得性体细胞突变发生在某些血液恶性肿瘤中，特别是新生幼年粒单核细胞白血病（JMML）和某些实体瘤（如NB）中，尽管频率较低。在7个细胞系和30个RIMS新鲜肿瘤和25个细胞系和40个NB新鲜肿瘤中筛选PTPN 11突变时，我们在胚胎性RMS患者中鉴定了错义突变（A72 T）。在RMS样本中，我们还在I细胞系和I患者中检测到NRAS突变;这两种突变都发生在胚胎RMS中，并且没有PTPN 11突变。在NB中未检测到PTPN 11突变。在95个白血病细胞系和261例新鲜白血病标本中，有17例标本检测到9种错义突变，其中11例（50.0%）发生在JMML标本中，其他恶性血液病的错义突变频率较低。此外，我们在5例JMML样本中发现了4例（18.2%）NRAS突变和1例（4.5%）KRAS突变，其中1例伴有PTPN 11突变。我们的数据表明PTPN 11和RAS的突变不仅在骨髓性血液系统恶性肿瘤的发病机制中起作用，而且在RMS恶性肿瘤的一个子集中也起作用。(c)2006威利-利斯公司
PTPN11 has been identified as a causative gene in Noonan syndrome (NS), responsible for about 50% of cases of NS. Given the association between NS and an increased risk of some malignancies, notably leukemia and probably some solid tumors including neuroblastoma (NB) and rhabdomyosarcoma (RMS), recent studies have reported that gain-of-function somatic mutations in PTPN11 occur in some hematological malignancies, especially de novo juvenile myelomonocytic leukemia (JMML) and in some solid tumors such as NB, although at a low frequency. In a screen for mutations of PTPN11 in 7 cell lines and 30 fresh tumors of RIMS and in 25 cell lines and 40 fresh tumors of NB, we identified a missense mutation (A72T) in an embryonal RMS patient. In the RMS samples, we also detected mutations of NRAS in I cell line and I patient; both mutations were in embryonal RMSs and had no PTPN11 mutations. No mutations of PTPN11 were detected in NB. In 95 leukemia cell lines and 261 fresh leukemia samples including 22 JMMLs, 9 kinds of missense mutations were detected in 17 leukemia samples, which included 11 (50.0%) mutations in JMML samples and lower frequencies in other hematological malignancies. Furthermore, we identified 4 (18.2%) NRAS mutations and 1 (4.5%) KRAS mutation in 5 JMML samples, 1 of which had a concomitant PTPN11 mutation. Our data suggest that mutations of PTPN11 as well as RAS play a role in the pathogenesis of not only myeloid hematological malignancies but also a subset of RMS malignancies. (c) 2006 Wiley-Liss, Inc.