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

Cell
Authors
Keywords
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.

Year of Publication
2014
Journal
Cell
Volume
156
Issue
6
Pages
1298-311
Date Published
2014 Mar 13
ISSN
1097-4172
URL
DOI
10.1016/j.cell.2014.02.031
PubMed ID
24630729
PubMed Central ID
PMC4040459
Links
Grant list
U54 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