title: Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing.
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.
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: McFadden
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Thales
authors.initials: T
authors.lastname: Papagiannakopoulos
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Chip
authors.initials: C
authors.lastname: Stewart
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Bhutkar
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: McKenna
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Dooley
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Vernon
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Malstrom
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Heimann
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Park
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Frances
authors.initials: F
authors.lastname: Chen
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Anna F
authors.initials: AF
authors.lastname: Farago
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Talya
authors.initials: T
authors.lastname: Dayton
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Shefler
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: 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.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: 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.
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D004195:Disease Models, Animal; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008207:Lymphatic Metastasis; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000473:pathology* / Q000556:secondary
chemical_list: D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse