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Identification of tumorigenic and therapeutically actionable mutations in transplantable mouse tumor cells by exome sequencing.

Journal article
Authors Joydeep Bhadury
Marcela Davila Lopez
Somsundar Veppil Muralidharan
Lisa M Nilsson
Jonas A Nilsson
Published in Oncogenesis
Volume 2
Pages e44
ISSN 2157-9024
Publication year 2013
Published at Institute of Clinical Sciences, Department of Surgery
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages e44
Language en
Links dx.doi.org/10.1038/oncsis.2013.8
Keywords next-generation sequencing; mouse tumors; Colon 26; L1210; Panc02; drug screen
Subject categories Surgery

Abstract

Cancer development occurs in response to the successive accumulation of mutations that eventually targets key regulators of cell proliferation. As most mutations likely occur randomly, cancer driver mutations can only be found if they are recurrent. Here we use exome sequencing of the mouse cell lines Panc02, L1210 and Colon 26 to identify genetic alterations (single-nucleotide polymorphisms and small insertion and deletions) that occurred in three different strains of mice and that resulted in tumorigenesis. We identify known mutations in genes like Kras, Cdkn2a/b, Smad4 and Trp53 and a large list of genes whose causal link to cancer is unknown. Interestingly, by screening a compound library we find that the identified oncogenic Kras mutation in Colon 26 cells correlates with its sensitivity to MEK inhibitors in vitro and in vivo. Our analysis of these mouse tumor exomes show that their manageable number of mutations could facilitate the identification of novel mutations or pathways driving tumor development. Furthermore, their use as tools is now enhanced as they can be used to create syngenic transplant models for utilization in drug discovery and validation. Finally, by showing that Kras mutant Colon 26 cells are sensitive to MEK inhibitors, we provide one proof-of-principle experiment that a platform containing targeted resequencing and drug screens could be a valuable addition in the clinic to devise anti-cancer drug schemes.

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