TY - JOUR
T1 - Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing
AU - McFadden, David G.
AU - Papagiannakopoulos, Thales
AU - Taylor-Weiner, Amaro
AU - Stewart, Chip
AU - Carter, Scott L.
AU - Cibulskis, Kristian
AU - Bhutkar, Arjun
AU - McKenna, Aaron
AU - Dooley, Alison
AU - Vernon, Amanda
AU - Sougnez, Carrie
AU - Malstrom, Scott
AU - Heimann, Megan
AU - Park, Jennifer
AU - Chen, Frances
AU - Farago, Anna F.
AU - Dayton, Talya
AU - Shefler, Erica
AU - Gabriel, Stacey
AU - Getz, Gad
AU - Jacks, Tyler
N1 - Funding Information:
We acknowledge Denise Crowley and the Swanson Biotechnology Core Facility for histology preparation and IHC; Harold Varmus, Nadya Dimitrova, and Eric L. Snyder for critical review of the manuscript; and Peter Campbell for a fruitful discussion. This work was supported by the Ludwig Center for Molecular Oncology at MIT (to T.J.), the Howard Hughes Medical Institute (to T.J.), the National Human Genome Research Institute (to S.G. and G.G.), NIH-NCI Career Development award K08CA160658 (to D.G.M.), and a Hope Funds for Cancer Research Fellowship (to T.P.). G.G. is the Paul C. Zamecnik, MD, Chair in Oncology at Massachusetts General Hospital. T.J. is the David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar at MIT. The authors wish to dedicate this paper to the memory of Officer Sean Collier, for his caring service to the MIT community and for his sacrifice.
PY - 2014/3/13
Y1 - 2014/3/13
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84896333670
U2 - 10.1016/j.cell.2014.02.031
DO - 10.1016/j.cell.2014.02.031
M3 - Article
C2 - 24630729
AN - SCOPUS:84896333670
SN - 0092-8674
VL - 156
SP - 1298
EP - 1311
JO - Cell
JF - Cell
IS - 6
ER -