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Genetic and Clonal Dissection of Murine Small Cell Lung Carcinoma Progression by Genome Sequencing

Author(s)
Taylor-Weiner, Amaro; Stewart, Chip; Carter, Scott L.; Cibulskis, Kristian; McKenna, Aaron; Dooley, Alison; Sougnez, Carrie; Park, Jennifer; Farago, Anna F.; Dayton, Talya; Shefler, Erica; Gabriel, Stacey; Getz, Gad; McFadden, David Glenn; Papagiannakopoulos, Thales; Bhutkar, Arjun; Vernon, Amanda; Malstrom, Scott E.; Heimann, Megan Kristianne; Parker, Jennifer E.; Chen, Frances K.; Jacks, Tyler E.; ... Show more Show less
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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
Date issued
2014-03
URI
http://hdl.handle.net/1721.1/110469
Department
Koch Institute for Integrative Cancer Research at MIT
Journal
Cell
Publisher
Elsevier
Citation
McFadden, David G.; Papagiannakopoulos, Thales; Taylor-Weiner, Amaro; Stewart, Chip; Carter, Scott L.; Cibulskis, Kristian; Bhutkar, Arjun et al. “Genetic and Clonal Dissection of Murine Small Cell Lung Carcinoma Progression by Genome Sequencing.” Cell 156, 6 (March 2014): 1298–1311 © 2014 Elsevier Inc
Version: Author's final manuscript
ISSN
0092-8674
1097-4172

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