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Nature:小细胞肺癌的遗传原因

摘要 : 对110个小细胞肺癌病例所做的全基因组测序,显示了几乎所有病例中肿瘤抑制因子基因TP53和RB1的一个典型的双等位基因失活现象。在TP53 和RB1没有发生改变的仅有的两个样本中,“染色体碎裂”(chromothripsis)将 “cyclin D1”激活,导致同样的分子效应。

 对110个小细胞肺癌病例所做的全基因组测序,显示了几乎所有病例中肿瘤抑制因子基因TP53和RB1的一个典型的双等位基因失活现象。在TP53 和RB1没有发生改变的仅有的两个样本中,“染色体碎裂”(chromothripsis)将 “cyclin D1”激活,导致同样的分子效应。另外,25%的肿瘤在NOTCH家族的基因中携带能造成失活的突变,同时作者也发现,一个临床前小鼠模型中Notch信号作用的激活可以降低肿瘤数量和延长突变小鼠的生存时间。这项研究突显了作为最具致命性的人类癌症之一的这种肺癌的可能的药物作用目标。

原文标题:Comprehensive genomic profiles of small cell lung cancer

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 andRB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressorsTP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.

来源: Nature 浏览次数:0

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