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Cell DOI:10.1016/j.cell.2014.02.031

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

Publication TypeJournal Article
Year of Publication2014
AuthorsMcFadden, DG, Papagiannakopoulos, T, Taylor-Weiner, A, Stewart, C, Carter, SL, Cibulskis, K, Bhutkar, A, McKenna, A, Dooley, A, Vernon, A, Sougnez, C, Malstrom, S, Heimann, M, Park, J, Chen, F, Farago, AF, Dayton, T, Shefler, E, Gabriel, S, Getz, G, Jacks, T
JournalCell
Volume156
Issue6
Pages1298-311
Date Published2014 Mar 13
ISSN1097-4172
KeywordsAnimals, Carcinogenesis, Disease Models, Animal, Humans, Liver Neoplasms, Lung Neoplasms, Lymphatic Metastasis, Mice, PTEN Phosphohydrolase, Small Cell Lung Carcinoma
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)00230-X
DOI10.1016/j.cell.2014.02.031
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24630729?dopt=Abstract

Alternate JournalCell
PubMed ID24630729
PubMed Central IDPMC4040459
Grant ListU54 HG003067 / HG / NHGRI NIH HHS / United States
T32 GM007484 / GM / NIGMS NIH HHS / United States
K08CA160658 / CA / NCI NIH HHS / United States
K08 CA160658 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States