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Cell. 2014 Mar 13;156(6):1298-311. doi: 10.1016/j.cell.2014.02.031.

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

Author information

1
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
2
Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
3
Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: gadgetz@broadinstitute.org.
4
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: tjacks@mit.edu.

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.

PMID:
24630729
PMCID:
PMC4040459
DOI:
10.1016/j.cell.2014.02.031
[Indexed for MEDLINE]
Free PMC Article
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