Journal article
Single allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer
Nature communications, Vol.12(1), pp.5238-5238
09/02/2021
DOI: 10.1038/s41467-021-25467-w
PMCID: PMC8413298
PMID: 34475389
Abstract
The most common events in breast cancer (BC) involve chromosome arm losses and gains. Here we describe identification of 1089 gene-centric common insertion sites (gCIS) from transposon-based screens in 8 mouse models of BC. Some gCIS are driver-specific, others driver non-specific, and still others associated with tumor histology. Processes affected by driver-specific and histology-specific mutations include well-known cancer pathways. Driver non-specific gCIS target the Mediator complex, Ca++ signaling, Cyclin D turnover, RNA-metabolism among other processes. Most gCIS show single allele disruption and many map to genomic regions showing high-frequency hemizygous loss in human BC. Two gCIS, Nf1 and Trps1, show synthetic haploinsufficient tumor suppressor activity. Many gCIS act on the same pathway responsible for tumor initiation, thereby selecting and sculpting just enough and just right signaling. These data highlight similar to 1000 genes with predicted conditional haploinsufficient tumor suppressor function and the potential to promote chromosome arm loss in BC.
Details
- Title: Subtitle
- Single allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer
- Creators
- Nathan F. Schachter - University of TorontoJessica R. Adams - University of TorontoPatryk Skowron - Hospital for Sick ChildrenKatelyn J. Kozma - University of TorontoChristian A. Lee - Ontario Institute for Cancer ResearchNandini Raghuram - University of TorontoJoanna Yang - University of TorontoAmanda J. Loch - Hospital for Sick ChildrenWei Wang - Hospital for Sick ChildrenAaron Kucharczuk - University of TorontoKatherine L. Wright - University of TorontoRita M. Quintana - Hospital for Sick ChildrenYeji An - University of TorontoDaniel Dotzko - Hospital for Sick ChildrenJennifer L. Gorman - Lunenfeld-Tanenbaum Research InstituteDaria Wojtal - University of TorontoJuhi S. Shah - Hospital for Sick ChildrenPaul Leon-Gomez - Hospital for Sick ChildrenGiovanna Pellecchia - Hospital for Sick ChildrenAdam J. Dupuy - Roy J. and Lucille A. Carver College of MedicineCharles M. Perou - University of North Carolina at Chapel HillIttai Ben-Porath - Hebrew University of JerusalemRotem Karni - Hebrew University of JerusalemEldad Zacksenhaus - University of TorontoJim R. Woodgett - Univ Toronto, Dept Med Biophys, Toronto, ON, CanadaSusan J. Done - University of TorontoLivia Garzia - McGill UniversityA. Sorana Morrissy - University of CalgaryJuri Reimand - Ontario Institute for Cancer ResearchMichael D. Taylor - Hospital for Sick ChildrenSean E. Egan - University of Toronto
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.12(1), pp.5238-5238
- DOI
- 10.1038/s41467-021-25467-w
- PMID
- 34475389
- PMCID
- PMC8413298
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- NATURE PORTFOLIO
- Number of pages
- 19
- Grant note
- CDMRP/US Army Department of Defence Canadian Breast Cancer Foundation/Canadian Cancer Society Research Institute The Joint Canada-Israel Health Research Program Canada's International Development Research Centre RGPIN-2016-06485 / Natural Sciences and Engineering Research Council of Canada (NSERC) Canadian Institutes of Health Research; Canadian Institutes of Health Research (CIHR) Terry Fox Foundation
- Language
- English
- Date published
- 09/02/2021
- Academic Unit
- Anatomy and Cell Biology; Pathology
- Record Identifier
- 9984284344702771
Metrics
10 Record Views