A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS-Driven Lung Cancer
| Autor: | Emily G. Shuldiner, Nicholas W. Hughes, Wen-Yang Lin, Su Kit Chew, Dmitri A. Petrov, Rui Tang, Leo C Chen, Min K. Tsai, King L. Hung, Emily L. Ashkin, Monte M. Winslow, Christopher D. McFarland, Chuan Li, Shi Ya C. Lee, Laura Andrejka, Charles Swanton, Maryam Yousefi, Le Cong, Hongchen Cai, Christopher W. Murray, Christian A. Kunder |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer genome sequencing Lung Neoplasms Oncology and Carcinogenesis Tumor initiation Biology medicine.disease_cause Cell Transformation Article law.invention Proto-Oncogene Proteins p21(ras) 03 medical and health sciences 0302 clinical medicine Rare Diseases law medicine Genetics 2.1 Biological and endogenous factors Humans Genes Tumor Suppressor Aetiology Lung cancer Gene Lung Cancer Neoplastic Lung Cancer Human Genome medicine.disease 030104 developmental biology Cell Transformation Neoplastic Oncology Genes 030220 oncology & carcinogenesis Cancer research Suppressor KRAS Carcinogenesis Tumor Suppressor Biotechnology |
| Zdroj: | Cancer Discov Cancer discovery, vol 11, iss 7 Cancer Discovery |
| ISSN: | 2159-8290 |
| Popis: | Cancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multistep process, but the importance and specific roles of many of these genes during tumor initiation, growth, and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS–driven lung cancer to quantify the impact of 48 known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer in vivo. Inactivation of some genes substantially increased growth, whereas the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional in vivo analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression. Significance: Our high-throughput and high-resolution analysis of tumor suppression uncovered novel genetic determinants of oncogenic KRAS–driven lung cancer initiation, overall growth, and exceptional growth. This taxonomy is consistent with changing constraints during the life history of cancer and highlights the value of quantitative in vivo genetic analyses in autochthonous cancer models. This article is highlighted in the In This Issue feature, p. 1601 |
| Databáze: | OpenAIRE |
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