Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cell. 2014 Mar 13;156(6):1298-1311. doi: 10.1016/j.cell.2014.02.031.
Small cell lung carcinoma (SCLC) is a highly lethal, smoking-associated cancer with few known targetable genetic alterations. Using genome sequencing, we characterized the somatic evolution of a genetically engineered mouse model (GEMM) of SCLC initiated by loss of Trp53 and Rb1. We identified alterations in DNA copy number and complex genomic rearrangements and demonstrated a low somatic point mutation frequency in the absence of tobacco mutagens. Alterations targeting the tumor suppressor Pten occurred in the majority of murine SCLC studied, and engineered Pten deletion accelerated murine SCLC and abrogated loss of Chr19 in Trp53; Rb1; Pten compound mutant tumors. Finally, we found evidence for polyclonal and sequential metastatic spread of murine SCLC by comparative sequencing of families of related primary tumors and metastases. We propose a temporal model of SCLC tumorigenesis with implications for human SCLC therapeutics and the nature of cancer-genome evolution in GEMMs.
小细胞肺癌（SCLC）是一种高度致命的、与吸烟有关的癌症，其可靶向的遗传改变很少。我们使用基因组测序，对由 Trp53 和 Rb1 缺失引发的 SCLC 基因工程小鼠模型（GEMM）的体细胞进化进行了特征描述。我们发现了 DNA 拷贝数的改变和复杂的基因组重排，并证明在没有烟草诱变剂的情况下，体细胞点突变频率较低。在大多数研究的鼠 SCLC 中，靶向肿瘤抑制因子 Pten 的改变发生，并且工程化的 Pten 缺失加速了鼠 SCLC 的发展，并消除了 Trp53；Rb1；Pten 复合突变肿瘤中 Chr19 的缺失。最后，我们通过对相关原发性肿瘤和转移瘤家族的比较测序，发现了鼠 SCLC 多克隆和顺序转移扩散的证据。我们提出了一个 SCLC 肿瘤发生的时间模型，对人类 SCLC 治疗和 GEMM 中癌症基因组进化的性质具有启示意义。
