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

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 lin...

Full description

Bibliographic Details
Main Authors:	Bhadury, J, López, M D, Muralidharan, S V, Nilsson, L M, Nilsson, J A
Format:	Online
Language:	English
Published:	Nature Publishing Group 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641362/

id	pubmed-3641362
recordtype	oai_dc
spelling	pubmed-36413622013-05-02 Identification of tumorigenic and therapeutically actionable mutations in transplantable mouse tumor cells by exome sequencing Bhadury, J López, M D Muralidharan, S V Nilsson, L M Nilsson, J A Short Communication 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. Nature Publishing Group 2013-04 2013-04-15 /pmc/articles/PMC3641362/ /pubmed/23588493 http://dx.doi.org/10.1038/oncsis.2013.8 Text en Copyright © 2013 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Bhadury, J López, M D Muralidharan, S V Nilsson, L M Nilsson, J A
spellingShingle	Bhadury, J López, M D Muralidharan, S V Nilsson, L M Nilsson, J A Identification of tumorigenic and therapeutically actionable mutations in transplantable mouse tumor cells by exome sequencing
author_facet	Bhadury, J López, M D Muralidharan, S V Nilsson, L M Nilsson, J A
author_sort	Bhadury, J
title	Identification of tumorigenic and therapeutically actionable mutations in transplantable mouse tumor cells by exome sequencing
title_short	Identification of tumorigenic and therapeutically actionable mutations in transplantable mouse tumor cells by exome sequencing
title_full	Identification of tumorigenic and therapeutically actionable mutations in transplantable mouse tumor cells by exome sequencing
title_fullStr	Identification of tumorigenic and therapeutically actionable mutations in transplantable mouse tumor cells by exome sequencing
title_full_unstemmed	Identification of tumorigenic and therapeutically actionable mutations in transplantable mouse tumor cells by exome sequencing
title_sort	identification of tumorigenic and therapeutically actionable mutations in transplantable mouse tumor cells by exome sequencing
description	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.
publisher	Nature Publishing Group
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641362/
_version_	1611974217484468224

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

Similar Items