Yamamoto Hiromasa, Shigematsu Hisayuki, Nomura Masaharu, Lockwood William W, Sato Mitsuo, Okumura Naoki, Soh Junichi, Suzuki Makoto, Wistuba Ignacio I, Fong Kwun M, Lee Huei, Toyooka Shinichi, Date Hiroshi, Lam Wan L, Minna John D, Gazdar Adi F
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Dallas, TX 75390-8593, USA.
Cancer Res. 2008 Sep 1;68(17):6913-21. doi: 10.1158/0008-5472.CAN-07-5084.
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.
我们研究了肺癌中PIK3CA基因的突变频率、功能以及拷贝数增加情况。PIK3CA突变是人类癌症中最常见的基因变化之一。我们使用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）细胞系以及691例切除的NSCLC肿瘤，分析了PIK3CA基因第9和20外显子的突变状态及基因拷贝数，并研究了PIK3CA改变与表皮生长因子受体（EGFR）信号通路基因（EGFR、KRAS、HER2和BRAF）突变状态之间的关系。我们还测定了PIK3CA的表达和活性，并将研究结果与对细胞生长的影响进行关联分析。我们在所有主要组织学类型的4.7%的NSCLC细胞系和1.6%的肿瘤中发现了突变。小细胞来源的细胞系中的突变仅限于两个ExPuSC细胞系。PIK3CA拷贝数增加在鳞状细胞癌（33.1%）中比在腺癌（6.2%）或SCLC细胞系（4.7%）中更常见。PIK3CA的突变状态与EGFR或KRAS并非相互排斥。PIK3CA改变与磷脂酰肌醇3激酶活性增加和磷酸化Akt表达相关。RNA干扰介导的PIK3CA基因敲低抑制了具有PIK3CA突变或拷贝数增加的细胞系的集落形成，但对PIK3CA野生型细胞无效。PIK3CA突变或拷贝数增加存在于一部分肺癌中，并且具有功能重要性。
