Somatic mutations of BECN1, an autophagy-related gene, in human cancers
Somatic mutations of BECN1, an autophagy-related gene, in human cancers
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DOI：
10.1111/j.1600-0463.2007.apm_640.x
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发表时间：
2007-06-01
期刊：
影响因子：
2.8
通讯作者：
Lee, Sug Hyung
中科院分区：
文献类型：
--
作者：
Lee, Jong Woo;Jeong, Eun Goo;Lee, Sug Hyung
逃避程序性细胞死亡（PCD）是人类癌症的标志之一。众所周知，细胞凋亡和自噬都是PCD的作用机制。BECN 1蛋白是自噬PCD的关键调节因子。编码BECN 1蛋白的BECN 1基因充当单倍不足肿瘤抑制基因。然而，迄今为止，缺乏关于人类癌症组织中BECN 1突变的数据。为了探讨BECN 1基因的体细胞突变可能有助于人类癌症发展的可能性，我们分析了人类BECN 1基因的整个编码区和所有剪接位点，用于检测180例胃癌，94例乳腺癌，50例急性白血病，50例结直肠癌，50例肝细胞癌，通过单链构象多态性（SSCP）和DNA测序对124例非小细胞肺癌进行了检测。共检测到11个BECN 1基因的体细胞突变，包括3个编码序列的错义突变（N8K，P350R和R389C）和8个内含子突变。在5例胃癌、3例结直肠癌、1例肺癌和1例乳腺癌中观察到突变。我们在HT 1080细胞中表达了三种突变（N8K，P350R和R389C），发现其中两种（P350R和R389C）与野生型BECN 1相比仅显示出轻微的细胞死亡活性降低。这是第一份关于人类癌症组织中BECN 1基因突变的报告，数据表明点突变在常见的人类癌症中是罕见的事件，可能在癌症发病机制中不起主要作用。
Evasion of programmed cell death (PCD) is one of the hallmarks of human cancers. It is well known that not only apoptosis, but also autophagy, acts as an action mechanism of PCD. BECN1 protein is a key regulator of autophagic PCD. The BECN1 gene that encodes BECN1 protein acts as a haploinsufficient tumor-suppressor gene. However, to date, data on BECN1 mutation in human cancer tissues are lacking. To explore the possibility that somatic mutation of the BECN1 gene might contribute to the development of human cancers, we analyzed the entire coding region and all splice sites of the human BECN1 gene for detection of somatic mutations in 180 gastric carcinomas, 94 breast carcinomas, 50 acute leukemias, 50 colorectal carcinomas, 50 hepatocellular carcinomas, and 124 non-small cell lung cancers by single-strand conformation polymorphism (SSCP) and DNA sequencing. Overall, we detected 11 somatic mutations of the BECN1 gene, including 3 missense mutations (N8K, P350R and R389C) in coding sequences and 8 mutations in introns. The mutations were observed in five gastric, three colorectal, one lung and one breast carcinoma (s). We expressed the three mutations (N8K, P350R and R389C) in HT1080 cells, and found that two (P350R and R389C) of them showed only slightly decreased cell death activities compared to the wild-type BECN1. This is the first report on BECN1 gene mutations in human cancer tissues, and the data suggest that point mutations are a rare event in common human cancers and probably do not play a major role in cancer pathogenesis.