Widespread selection for oncogenic mutant allele imbalance in cancer Journal Article
| Authors: | Bielski, C. M.; Donoghue, M. T. A.; Gadiya, M.; Hanrahan, A. J.; Won, H. H.; Chang, M. T.; Jonsson, P.; Penson, A. V.; Gorelick, A.; Harris, C.; Schram, A. M.; Syed, A.; Zehir, A.; Chapman, P. B.; Hyman, D. M.; Solit, D. B.; Shannon, K.; Chandarlapaty, S.; Berger, M. F.; Taylor, B. S. |
| Article Title: | Widespread selection for oncogenic mutant allele imbalance in cancer |
| Abstract: | Driver mutations in oncogenes encode proteins with gain-of-function properties that enhance fitness. Heterozygous mutations are thus viewed as sufficient for tumorigenesis. We describe widespread oncogenic mutant allele imbalance in 13,448 prospectively characterized cancers. Imbalance was selected for through modest dosage increases of gain-of-fitness mutations. Negative selection targeted haplo-essential effectors of the spliceosome. Loss of the normal allele comprised a distinct class of imbalance driven by competitive fitness, which correlated with enhanced response to targeted therapies. In many cancers, an antecedent oncogenic mutation drove evolutionarily dependent allele-specific imbalance. In other instances, oncogenic mutations co-opted independent copy-number changes via the evolutionary process of exaptation. Oncogenic allele imbalance is a pervasive evolutionary innovation that enhances fitness and modulates sensitivity to targeted therapy. Copyright © 2018 Elsevier Inc. All rights reserved. |
| Keywords: | oncogenes; targeted therapy; selection; cancer; competitive fitness; exaptation |
| Journal Title: | Cancer Cell |
| Volume: | 34 |
| Issue: | 5 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2018-11-12 |
| Start Page: | 852 |
| End Page: | 862.e4 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2018.10.003 |
| PUBMED: | 30393068 |
| PROVIDER: | scopus |
| PMCID: | PMC6234065 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 December 2018 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work