PIK3CA mutations and copy number gains in human lung cancers.
PIK3CA mutations and copy number gains in human lung cancers.
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DOI：
10.1158/0008-5472.can-07-5084
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发表时间：
2008-09-01
期刊：
影响因子：
11.2
通讯作者：
Gazdar AF
中科院分区：
文献类型：
--
作者：
Yamamoto H;Shigematsu H;Nomura M;Lockwood WW;Sato M;Okumura N;Soh J;Suzuki M;Wistuba II;Fong KM;Lee H;Toyooka S;Date H;Lam WL;Minna JD;Gazdar AF
我们研究了肺癌组织中PIK3CA基因突变的频率和功能以及拷贝数的增加。PIK3CA突变是人类癌症中最常见的基因突变之一。我们分析了86个非小细胞肺癌(NSCLC)细胞系、43个小细胞肺癌(SCLC)细胞系、3个肺外小细胞癌(ExPuSC)细胞系和691例切除的NSCLC肿瘤组织中PIK3CA基因外显子9和20的突变状态和基因拷贝数，并研究了PIK3CA突变与表皮生长因子受体(EGFR)信号通路基因(EGFR、KRAS、HER2和BRAF)突变状态的关系。我们还检测了PIK3CA的表达和活性，并将结果与对细胞生长的影响相关联。我们在4.7%的非小细胞肺癌细胞系和1.6%的所有主要组织学类型的肿瘤中发现了突变。小细胞来源的细胞系的突变仅限于两个ExPuSC细胞系。PIK3CA拷贝数增加在鳞癌(33.1%)高于腺癌(6.2%)或小细胞肺癌(4.7%)。PIK3CA的突变状态与EGFR或KRAS不是互斥的。PIK3CA的改变与磷脂酰肌醇3-激酶活性和磷酸化Akt的表达增加相关。RNA干扰介导的PIK3CA基因敲除抑制了具有PIK3CA突变或获得的细胞系的集落形成，但对PIK3CA野生型细胞无效。PIK3CA突变或获得存在于肺癌的一个子集中，并且具有重要的功能。
We investigated the frequency and function of mutations and increased copy number of the PIK3CA gene in lung cancers. PIK3CA mutations are one of the most common gene changes present in human cancers. We analyzed the mutational status of exons 9 and 20 and gene copy number of PIK3CA using 86 non–small cell lung cancer (NSCLC) cell lines, 43 small cell lung cancer (SCLC) cell lines, 3 extrapulmonary small cell cancer (ExPuSC) cell lines, and 691 resected NSCLC tumors and studied the relationship between PIK3CA alterations and mutational status of epidermal growth factor receptor (EGFR) signaling pathway genes (EGFR, KRAS, HER2, and BRAF). We also determined PIK3CA expression and activity and correlated the findings with effects on cell growth. We identified mutations in 4.7% of NSCLC cell lines and 1.6% of tumors of all major histologic types. Mutations in cell lines of small cell origin were limited to two ExPuSC cell lines. PIK3CA copy number gains were more frequent in squamous cell carcinoma (33.1%) than in adenocarcinoma (6.2%) or SCLC lines (4.7%). Mutational status of PIK3CA was not mutually exclusive to EGFR or KRAS. PIK3CA alterations were associated with increased phosphatidylinositol 3-kinase activity and phosphorylated Akt expression. RNA interference–mediated knockdown of PIK3CA inhibited colony formation of cell lines with PIK3CA mutations or gains but was not effective in PIK3CA wild-type cells. PIK3CA mutations or gains are present in a subset of lung cancers and are of functional importance.