Dataset Information

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

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.

SUBMITTER: Bhadury J

PROVIDER: S-EPMC3641362 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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

Bhadury J J López M D MD Muralidharan S V SV Nilsson L M LM Nilsson J A JA

Oncogenesis 20130415

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 ...[more]

PMID: 23588493

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Project description:Tumor-only genomic profiling (TGP) is increasingly advocated for all patients with cancer given the possible therapeutic implications. It is critical to develop clinical algorithms to identify and address potentially actionable germline findings identified by TGP. A multidisciplinary team analyzed publicly available data for genes in which mutations are implicated in germline cancer susceptibility and established a pipeline to automate clinical referral for evaluation of TGP findings. A total of 2,308 patients underwent TGP, with 81 patients (3.5%) identified by the automatic referral pipeline; 37 patients (1.6%) were referred outside the pipeline based on concerns by the molecular geneticist, pathologist, or oncologist regarding genotype-phenotype correlation. Thirty-one patients (38%) and 17 patients (46%) underwent germline testing from the automatic pipeline and other referrals, respectively, and of these patients, 23 (72%) and four (24%) had confirmed germline pathogenic variants (GPVs), respectively. The majority of confirmed GPVs were in automatic referral genes, with BRCA2 being most common (confirmed GPVs in 11 [85%] of 13 patients tested), followed by PALB2 (five [67%] of six patients), BRCA1 (two [40%] of five patients), MSH6 (two of three patients), and MLH1 (two of two patients). Forty-eight percent of confirmed GPVs were found in tumors known to be associated with germline mutations in the gene. Germline testing was not performed in 50 (62%) of 81 patients identified by automatic referral as a result of poor patient health or death (30%), lack of follow-up (30%), and patient refusal (30%). Of patients undergoing TGP, 5% had somatic findings triggering referral, and implementation of an automatic referral pipeline based solely on gene versus other clinical or molecular features resulted in a 74% germline confirmation. However, only 41% of referred patients underwent germline testing. Systems-based approaches are needed to identify carriers of actionable germline cancer susceptibility mutations identified by TGP.

Dataset Information

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

Publications

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

Similar Datasets

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