Selection pressures of TP53 mutation and microenvironmental location influence epidermal growth factor receptor gene amplification in human glioblastomas.
Selection pressures of TP53 mutation and microenvironmental location influence epidermal growth factor receptor gene amplification in human glioblastomas.
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发表时间：
2003-01
期刊：
影响因子：
11.2
通讯作者：
Yoshifumi Okada;Edward E. Hurwitz;J. Esposito;M. Brower;C. Nutt;D. Louis
中科院分区：
文献类型：
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作者：
Yoshifumi Okada;Edward E. Hurwitz;J. Esposito;M. Brower;C. Nutt;D. Louis
表皮生长因子受体（EGFR）基因扩增在胶质母细胞瘤中发生，即所谓的双分钟。由于双分钟是染色体外片段，因此必须施加选择压力以在多次细胞分裂中维持高 EGFR 拷贝数。在胶质母细胞瘤裂解物的分析中，几乎只在含有野生型 TP53 基因的胶质母细胞瘤中观察到 EGFR 扩增，这提出了另一种假设：TP53 突变要么阻止扩增，要么选择不维持 EGFR 扩增细胞。为了在细胞水平上解决这些可能性，我们研究了 14 种胶质母细胞瘤的 TP53 突变和 EGFR 基因扩增状态，对后者使用荧光原位杂交 (FISH)。值得注意的是，6个TP53突变病例中有4个在不同区域分离出EGFR扩增细胞，表明EGFR扩增在TP53突变胶质母细胞瘤的细胞水平上频繁发生。因此，TP53突变不会阻止EGFR扩增，但不会促进EGFR扩增细胞的选择。在 8 例没有 TP53 突变的病例中，5 例存在广泛的 EGFR 扩增。在这五例中的四例中，肿瘤的多个区域可供检查； FISH 证明了 EGFR 扩增的分级，其中高度扩增的细胞主要位于侵袭边缘而不是相对实体的肿瘤中心，这表明当选择用于体内时，EGFR 过度表达可能与肿瘤侵袭有关。
Epidermal growth factor receptor (EGFR) gene amplification occurs in glioblastomas as so-called double minutes. Because double minutes are extrachromosomal fragments, selection pressures must operate to maintain high EGFR copy number over multiple cell divisions. In analyses of glioblastoma lysates, EGFR amplification has been observed almost exclusively in glioblastomas harboring wild-type TP53 genes, which raises the alternative hypotheses that TP53 mutation either prevents amplification or selects against maintenance of EGFR-amplified cells. To address these possibilities at the cellular level, we studied 14 glioblastomas for TP53 mutation and EGFR gene amplification status, using fluorescence in situ hybridization (FISH) for the latter. Remarkably, four of the six cases with TP53 mutation had isolated EGFR-amplified cells in different regions, demonstrating that EGFR amplification occurs frequently at the cellular level in TP53-mutant glioblastomas. Thus, TP53 mutation does not prevent EGFR amplification but does not facilitate selection of EGFR-amplified cells. Of the eight cases without TP53 mutation, five had widespread EGFR amplification. In four of these five cases, multiple regions of the tumor were available for examination; FISH demonstrated a gradation of EGFR amplification, with highly amplified cells, primarily at the invading edges rather than the relatively solid tumor centers, suggesting that EGFR overexpression, when selected for in vivo, may be related to tumor invasion.