Single allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer
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 ~1000 genes with predicted conditional haploinsufficient tumor suppressor function and the potential to promote chromosome arm loss in BC.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 02, 2021
- Source ID
- 10.1038/s41467-021-25467-w
Entities
People
- Aaron Kucharczuk
- Adam J. Dupuy
- Amanda J. Loch
- Charles M. Perou
- Christian A. Lee
- Daniel Dotzko
- Daria Wojtal
- Eldad Zacksenhaus
- Giovanna Pellecchia
- Ittai Ben-porath
- Jennifer L. Gorman
- Jessica R. Adams
- Jim R. Woodgett
- Joanna Yang
- Juhi S. Shah
- Jüri Reimand
- Katelyn. J. Kozma
- Katherine L. Wright
- Livia Garzia
- Michael D. Taylor
- Nandini Raghuram
- Nathan F. Schachter
- Patryk Skowron
- Paúl León-Goméz
- Rita M. Quintana
- Rotem Karni
- Sean E. Egan
- Sorana Morrissy
- Susan J. Done
- Wei Wang
- Yeji An
Organizations
- Canadian Cancer Society Research Institute
- Canadian Institutes of Health Research
- Canadian International Development Agency
- Congressionally Directed Medical Research Programs
- Terry Fox foundation