Genetic and Clonal Dissection of Murine Small Cell Lung Carcinoma Progression by Genome Sequencing
Menée à l'aide d'un modèle murin génétiquement modifié, cette étude met en évidence des anomalies génomiques dans les tumeurs primitives et les métastases, puis propose un modèle temporel de l'évolution clonale d'un cancer du poumon à petites cellules
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. "Murine SCLCs acquire few point mutations in the absence of tobacco mutagens "Pten is recurrently mutated, and engineered deletion accelerates tumor progression "Mycl1 amplifications play an early, central role in mSCLC tumorigenesis "Analysis of related primary and metastatic mSCLC suggests complex clonal evolution Comprehensive genomic analysis in a mouse model of small-cell lung carcinoma delineates metastatic progression in this tumor type, showing that selection for specific cancer mutations can drive large genomic rearrangements and that distant metastases likely arise from a common metastatic seeding step involving the lymph nodes.
Cell 2014