Genetic and Clonal Dissection of Murine Small Cell Lung Carcinoma Progression by Genome Sequencing
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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
Date Issued
March 2014
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
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
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.cell.2014.02.031
