CBL is frequently altered in lung cancers: its relationship to mutations in MET and EGFR tyrosine kinases.
CBL is frequently altered in lung cancers: its relationship to mutations in MET and EGFR tyrosine kinases.
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DOI：
10.1371/journal.pone.0008972
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发表时间：
2010-01-29
期刊：
影响因子：
3.7
通讯作者：
Salgia R
中科院分区：
文献类型：
--
作者：
Tan YH;Krishnaswamy S;Nandi S;Kanteti R;Vora S;Onel K;Hasina R;Lo FY;El-Hashani E;Cervantes G;Robinson M;Hsu HS;Kales SC;Lipkowitz S;Karrison T;Sattler M;Vokes EE;Wang YC;Salgia R
非小细胞肺癌 (NSCLC) 是一组具有多种遗传和蛋白质组改变的异质性疾病。 c-CBL 是一种 E3 泛素连接酶和接头分子，对于正常体内平衡和癌症非常重要。我们确定了 c-CBL 的遗传变异、与受体酪氨酸激酶（EGFR 和 MET）的关系以及 NSCLC 中的功能。使用档案福尔马林固定石蜡包埋 (FFPE) 提取的基因组 DNA，我们发现 c-CBL 突变以体细胞方式发生在肺癌中。 c-CBL 突变与 MET 或 EGFR 突变并不相互排斥；然而，它们与 p53 和 KRAS 突变无关。在正常/肿瘤成对分析中，c-CBL 基因座杂合性 (LOH) 显着丢失（22%，n = 8/37），并且这些样本均未显示 c-CBL 剩余副本中存在任何突变。 c-CBL LOH 还与同一样本中观察到的 EGFR 和 MET 突变呈正相关。使用选定的 c-CBL 体细胞突变，如 S80N/H94Y、Q249E 和 W802*（分别从白种人、台湾人和非裔美国人样本中获得）转染 NSCLC 细胞系，细胞活力和细胞运动性增加。将c-CBL的总体突变率作为体细胞错义突变和LOH的组合，显然c-CBL在肺癌中高度突变，可能在肺部肿瘤的发生和转移中发挥重要作用。
Non-small cell lung cancer (NSCLC) is a heterogeneous group of disorders with a number of genetic and proteomic alterations. c-CBL is an E3 ubiquitin ligase and adaptor molecule important in normal homeostasis and cancer. We determined the genetic variations of c-CBL, relationship to receptor tyrosine kinases (EGFR and MET), and functionality in NSCLC. Using archival formalin-fixed paraffin embedded (FFPE) extracted genomic DNA, we show that c-CBL mutations occur in somatic fashion for lung cancers. c-CBL mutations were not mutually exclusive of MET or EGFR mutations; however they were independent of p53 and KRAS mutations. In normal/tumor pairwise analysis, there was significant loss of heterozygosity (LOH) for the c-CBL locus (22%, n = 8/37) and none of these samples revealed any mutation in the remaining copy of c-CBL. The c-CBL LOH also positively correlated with EGFR and MET mutations observed in the same samples. Using select c-CBL somatic mutations such as S80N/H94Y, Q249E and W802* (obtained from Caucasian, Taiwanese and African-American samples, respectively) transfected in NSCLC cell lines, there was increased cell viability and cell motility. Taking the overall mutation rate of c-CBL to be a combination as somatic missense mutation and LOH, it is clear that c-CBL is highly mutated in lung cancers and may play an essential role in lung tumorigenesis and metastasis.
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影响因子：
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作者：
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