Lee Jong Woo, Jeong Eun Goo, Lee Sung Hak, Yoo Nam Jin, Lee Sug Hyung
Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
APMIS. 2007 Jun;115(6):750-6. doi: 10.1111/j.1600-0463.2007.apm_640.x.
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.
逃避程序性细胞死亡（PCD）是人类癌症的标志之一。众所周知，不仅凋亡，而且自噬都作为PCD的作用机制。BECN1蛋白是自噬性PCD的关键调节因子。编码BECN1蛋白的BECN1基因作为单倍体不足的肿瘤抑制基因发挥作用。然而，迄今为止，关于人类癌组织中BECN1突变的数据尚缺乏。为了探索BECN1基因的体细胞突变可能促成人类癌症发生发展的可能性，我们通过单链构象多态性（SSCP）和DNA测序分析了人类BECN1基因的整个编码区和所有剪接位点，以检测180例胃癌、94例乳腺癌、50例急性白血病、50例结直肠癌、50例肝细胞癌和124例非小细胞肺癌中的体细胞突变。总体而言，我们检测到BECN1基因的11个体细胞突变，包括编码序列中的3个错义突变（N8K、P350R和R389C）和内含子中的8个突变。这些突变在5例胃癌、3例结直肠癌、1例肺癌和1例乳腺癌中被观察到。我们在HT1080细胞中表达了这3个突变（N8K、P350R和R389C），发现其中2个（P350R和R389C）与野生型BECN1相比，细胞死亡活性仅略有下降。这是关于人类癌组织中BECN1基因突变的首次报告，数据表明点突变在常见人类癌症中是罕见事件，可能在癌症发病机制中不发挥主要作用。
