Kras mutant genetically engineered mouse models of human cancers are genomically heterogeneous
| العنوان: | Kras mutant genetically engineered mouse models of human cancers are genomically heterogeneous |
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| المؤلفون: | Jason E. Long, Bu-Er Wang, Florian Gnad, Oded Foreman, Melissa R. Junttila, Jason H. Cheng, Mallika Singh, Anneleen Daemen, Christopher Tran, Wei-Jen Chung, Jonathan E. Cooper, Zora Modrusan |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | National Academy of Sciences, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Multidisciplinary, Genomics, Computational biology, Biology, Biological Sciences, medicine.disease, medicine.disease_cause, Transcriptome, 03 medical and health sciences, 030104 developmental biology, PNAS Plus, Pancreatic cancer, Genetically Engineered Mouse, medicine, Genetics, Kras, genomics, cancer, mouse models, KRAS, heterogeneity, Carcinogenesis, Gene, Exome sequencing |
| الوصف: | Significance RAS mutant cancers represent a large unmet clinical need. Kras mutant genetically engineered mouse models (GEMMs) of cancer recapitulate disease characteristics and are relied upon preclinically to validate targets and test therapies. Our integrative analysis of GEMM tumors revealed significantly evolved genetic heterogeneity, a common feature of human tumors that undermines therapeutic responses. Moreover, interspecies comparative analyses showed the extent of gene-level fidelity between altered oncogenes and tumor suppressors. The genomic diversity represents an unrecognized opportunity to identify therapeutically susceptible genomic subsets preclinically. Moreover, this more-thorough understanding of the unappreciated complexity in these model systems ultimately allows for better interpretation and translatability of preclinical GEMM data for the benefit of cancer patients. KRAS mutant tumors are largely recalcitrant to targeted therapies. Genetically engineered mouse models (GEMMs) of Kras mutant cancer recapitulate critical aspects of this disease and are widely used for preclinical validation of targets and therapies. Through comprehensive profiling of exomes and matched transcriptomes of >200 KrasG12D-initiated GEMM tumors from one lung and two pancreatic cancer models, we discover that significant intratumoral and intertumoral genomic heterogeneity evolves during tumorigenesis. Known oncogenes and tumor suppressor genes, beyond those engineered, are mutated, amplified, and deleted. Unlike human tumors, the GEMM genomic landscapes are dominated by copy number alterations, while protein-altering mutations are rare. However, interspecies comparative analyses of the genomic landscapes demonstrate fidelity between genes altered in KRAS mutant human and murine tumors. Genes that are spontaneously altered during murine tumorigenesis are also among the most prevalent found in human indications. Using targeted therapies, we also demonstrate that this inherent tumor heterogeneity can be exploited preclinically to discover cancer-specific and genotype-specific therapeutic vulnerabilities. Focusing on Kras allelic imbalance, a feature shared by all three models, we discover that MAPK pathway inhibition impinges uniquely on this event, indicating distinct susceptibility and fitness advantage of Kras-mutant cells. These data reveal previously unknown genomic diversity among KrasG12D-initiated GEMM tumors, places them in context of human patients, and demonstrates how to exploit this inherent tumor heterogeneity to discover therapeutic vulnerabilities. |
| اللغة: | English |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ac5689d4ac61dca3c5066dc1b4f06a0e http://europepmc.org/articles/PMC5754767 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ac5689d4ac61dca3c5066dc1b4f06a0e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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