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. Dupuy; Charles 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

doi:10.1038/s41467-021-25467-w

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 journal › Article › peer-review

6 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 language	English
Article number	5238
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25467-w
State	Published - 2 Sep 2021

Bibliographical note

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-021-25467-w

Cite this

Schachter, N. F., Adams, J. R., Skowron, P., Kozma, K. J., Lee, C. A., Raghuram, N., Yang, J., Loch, A. J., Wang, W., Kucharczuk, A., Wright, K. L., Quintana, R. M., An, Y., Dotzko, D., Gorman, J. L., Wojtal, D., Shah, J. S., Leon-Gomez, P., Pellecchia, G., ... Egan, S. E. (2021). Single allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer. Nature Communications, 12(1), Article 5238. https://doi.org/10.1038/s41467-021-25467-w

@article{ace2eb4aea514d1c8f113de28e88377b,

title = "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.",

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

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = sep,

day = "2",

doi = "10.1038/s41467-021-25467-w",

language = "אנגלית",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Schachter, NF, Adams, JR, Skowron, P, Kozma, KJ, Lee, CA, Raghuram, N, Yang, J, Loch, AJ, Wang, W, Kucharczuk, A, Wright, KL, Quintana, RM, An, Y, Dotzko, D, Gorman, JL, Wojtal, D, Shah, JS, Leon-Gomez, P, Pellecchia, G, Dupuy, AJ, Perou, CM, Ben-Porath, I , Karni, R, Zacksenhaus, E, Woodgett, JR, Done, SJ, Garzia, L, Sorana Morrissy, A, Reimand, J, Taylor, MD & Egan, SE 2021, 'Single allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer', Nature Communications, vol. 12, no. 1, 5238. https://doi.org/10.1038/s41467-021-25467-w

TY - JOUR

T1 - Single allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer

AU - Schachter, Nathan F.

AU - Adams, Jessica R.

AU - Skowron, Patryk

AU - Kozma, Katelyn J.

AU - Lee, Christian A.

AU - Raghuram, Nandini

AU - Yang, Joanna

AU - Loch, Amanda J.

AU - Wang, Wei

AU - Kucharczuk, Aaron

AU - Wright, Katherine L.

AU - Quintana, Rita M.

AU - An, Yeji

AU - Dotzko, Daniel

AU - Gorman, Jennifer L.

AU - Wojtal, Daria

AU - Shah, Juhi S.

AU - Leon-Gomez, Paul

AU - Pellecchia, Giovanna

AU - Dupuy, Adam J.

AU - Perou, Charles M.

AU - Ben-Porath, Ittai

AU - Karni, Rotem

AU - Zacksenhaus, Eldad

AU - Woodgett, Jim R.

AU - Done, Susan J.

AU - Garzia, Livia

AU - Sorana Morrissy, A.

AU - Reimand, Jüri

AU - Taylor, Michael D.

AU - Egan, Sean E.

PY - 2021/9/2

Y1 - 2021/9/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85114624497&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-25467-w

DO - 10.1038/s41467-021-25467-w

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 34475389

AN - SCOPUS:85114624497

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5238

ER -

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

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this