Abstract 1084: Comprehensive genomic analysis of murine small cell lung carcinoma uncovers recurrent Pten alterations that drive tumor progression and alter tumor genome evolution.
Authors: McFadden David G. , Papagiannakopoulos Thales , Cibulskis Kristian , Stewart Chip , Carter Scott , Taylor-Weiner Amaro , Bhutkar Arjun , Sougnez Carrie , Dooley Alison , Shefler Erica , Lander Eric , Gabriel Stacey , Getz Gad , Jacks Tyler 
Published: August 2014

Small cell lung carcinoma (SCLC) is a highly lethal tumor for which few targetable genetic alterations have been identified. SCLC is tightly associated with an extended history of tobacco use, and recent DNA sequencing studies have revealed highly mutated SCLC cancer genomes. Interestingly, two studies analyzing the human SCLC genome report distinct sets of putative driver mutations, highlighting the challenge of identifying functional events in highly mutated cancers. In the absence of environmental mutagens, a previously established genetically engineered mouse model of SCLC initiated by combined loss of Trp53 and Rb1 recapitulates the salient clinical features of human SCLC including tumor histologic progression and frequent distant metastases. This model has been shown to acquire DNA copy number alterations shared with human SCLC, suggesting that cross-species cancer genomics may identify a subset of driver events in human cancers.

In order to characterize the spectrum of acquired events in murine SCLC and identify evolutionarily conserved drivers of SCLC progression, we define the somatic genome and transcriptome of a large panel of murine SCLC at single nucleotide resolution using exome, genome and RNA sequencing. We uncover complex subclonality in primary murine SCLC tumors and detect evidence for clonal selection during metastatic spread. As expected in the absence of environmental mutagens, we demonstrate a low somatic mutation frequency in murine SCLC. Using integrative genomic analyses we uncover alterations in chromatin remodeling enzymes and identify Pten as a critical tumor suppressor in this model. Engineered Pten deletion in murine SCLC dramatically accelerates tumorigenesis and fundamentally alters the genomic evolution of these tumors. This work represents the first large-scale comprehensive genomic characterization of a genetically engineered mouse cancer model at single nucleotide resolution, has implications for the nature of tumor evolution in mouse cancer models and identifies a potential therapeutic target in a subset of human SCLC.

Citation Format: David G. McFadden, Thales Papagiannakopoulos, Kristian Cibulskis, Chip Stewart, Scott Carter, Amaro Taylor-Weiner, Arjun Bhutkar, Carrie Sougnez, Alison Dooley, Erica Shefler, Eric Lander, Stacey Gabriel, Gad Getz, Tyler Jacks. Comprehensive genomic analysis of murine small cell lung carcinoma uncovers recurrent Pten alterations that drive tumor progression and alter tumor genome evolution. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1084. doi:10.1158/1538-7445.AM2013-1084