Single allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer

Nathan F. Schachter, Jessica R. Adams, Patryk Skowron, Katelyn J. Kozma, Christian A. Lee, Nandini Raghuram, Joanna Yang, Amanda J. Loch, Wei Wang, Aaron Kucharczuk, Katherine L. Wright, Rita M. Quintana, Yeji An, Daniel Dotzko, Jennifer L. Gorman, Daria Wojtal, Juhi S. Shah, Paul Leon-Gomez, Giovanna Pellecchia, Adam J. DupuyCharles M. Perou, Ittai Ben-Porath, Rotem Karni, Eldad Zacksenhaus, Jim R. Woodgett, Susan J. Done, Livia Garzia, A. Sorana Morrissy, Jüri Reimand, Michael D. Taylor, Sean E. Egan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageAmerican English
Article number5238
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - 2 Sep 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

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