Carretero Julian, Medina Pedro P, Pio Ruben, Montuenga Luis M, Sanchez-Cespedes Montserrat
Lymphoma and Lung Cancer Group, Molecular Pathology Program, Centro Nacional de Investigaciones Oncologicas, Calle Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Oncogene. 2004 May 13;23(22):4037-40. doi: 10.1038/sj.onc.1207502.
Germline mutations of the LKB1 gene are responsible for Peutz-Jeghers syndrome (PJS), an autosomal dominant inherited disorder bestowing an increased risk of cancer. We have recently demonstrated that LKB1 inactivating mutations are not confined to PJS, but also appear in lung adenocarcinomas of sporadic origin, including primary tumors and lung cancer cell lines. To accurately determine the frequency of inactivating LKB1 gene mutations in lung tumors we have sequenced the complete coding region of LKB1 in 21 additional lung cancer cell lines. Here we describe the mutational status of LKB1 gene in 30 lung cancer cell lines from different histopathological types, including 11 lung adenocarcinomas (LADs) and 11 small cell lung cancers (SCLCs). LKB1 gene alterations were present in six (54%) of the LAD cell lines tested but in none of the other histological types. Similar to our previous observations in primary tumors, all point mutations were of the nonsense or frameshift type, leading to an abnormal, truncated protein. Moreover, 2 cell lines (A427 and H2126) harbored large gene deletions that spanned several exons. Hence, we have identified additional lung cancer cell lines carrying inactivating mutations of the LKB1 tumor suppressor gene, further attesting to the significance of this gene in the development of LADs and providing new natural LKB1 knockouts for studies of the biological function of the LKB1 protein.
LKB1基因的种系突变是黑斑息肉综合征（PJS）的病因，这是一种常染色体显性遗传病，会增加患癌风险。我们最近证实，LKB1失活突变并不局限于PJS，在散发性起源的肺腺癌中也有出现，包括原发性肿瘤和肺癌细胞系。为了准确确定肺肿瘤中LKB1基因失活突变的频率，我们对另外21个肺癌细胞系的LKB1完整编码区进行了测序。在此，我们描述了30个来自不同组织病理学类型的肺癌细胞系中LKB1基因的突变状态，其中包括11个肺腺癌（LAD）细胞系和11个小细胞肺癌（SCLC）细胞系。在所检测的LAD细胞系中，有6个（54%）存在LKB1基因改变，而其他组织学类型中均未发现。与我们之前在原发性肿瘤中的观察结果相似，所有点突变均为无义或移码类型，导致产生异常的截短蛋白。此外，有2个细胞系（A427和H2126）存在跨越多个外显子的大片段基因缺失。因此，我们鉴定出了更多携带LKB1肿瘤抑制基因失活突变的肺癌细胞系，进一步证明了该基因在LAD发生发展中的重要性，并为研究LKB1蛋白的生物学功能提供了新的天然LKB1基因敲除模型。
