Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing

David G. McFadden, Thales Papagiannakopoulos, Amaro Taylor-Weiner, Chip Stewart, Scott L. Carter, Kristian Cibulskis, Arjun Bhutkar, Aaron McKenna, Alison Dooley, Amanda Vernon, Carrie Sougnez, Scott Malstrom, Megan Heimann, Jennifer Park, Frances Chen, Anna F. Farago, Talya Dayton, Erica Shefler, Stacey Gabriel, Gad GetzTyler Jacks

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1298-1311
Number of pages14
JournalCell
Volume156
Issue number6
DOIs
StatePublished - Mar 13 2014

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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McFadden, D. G., Papagiannakopoulos, T., Taylor-Weiner, A., Stewart, C., Carter, S. L., Cibulskis, K., Bhutkar, A., McKenna, A., Dooley, A., Vernon, A., Sougnez, C., Malstrom, S., Heimann, M., Park, J., Chen, F., Farago, A. F., Dayton, T., Shefler, E., Gabriel, S., ... Jacks, T. (2014). Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing. Cell, 156(6), 1298-1311. https://doi.org/10.1016/j.cell.2014.02.031