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Cancer drivers converge on NOTCH

Cancer genome–sequencing projects have emphasized the handful of genes mutated at high frequency in patients. Less attention has been directed to the hundreds of genes mutated in only a few patients—the so-called “long tail” mutations. Although rare, these mutations may nonetheless inform patient care. Loganathan et al. developed a reverse genetic CRISPR screen that allowed them to functionally assess in mice nearly 500 long tail gene mutations that occur in human head and neck squamous cell carcinoma (HNSCC). They identified 15 tumor-suppressor genes with activities that converged on the NOTCH signaling pathway. Given that NOTCH itself is mutated at high frequency in HNSCC, these results suggest that the growth of these tumors is largely driven by NOTCH inactivation.
Science, this issue p. 1264

Abstract

In most human cancers, only a few genes are mutated at high frequencies; most are mutated at low frequencies. The functional consequences of these recurrent but infrequent “long tail” mutations are often unknown. We focused on 484 long tail genes in head and neck squamous cell carcinoma (HNSCC) and used in vivo CRISPR to screen for genes that, upon mutation, trigger tumor development in mice. Of the 15 tumor-suppressor genes identified, ADAM10 and AJUBA suppressed HNSCC in a haploinsufficient manner by promoting NOTCH receptor signaling. ADAM10 and AJUBA mutations or monoallelic loss occur in 28% of human HNSCC cases and are mutually exclusive with NOTCH receptor mutations. Our results show that oncogenic mutations in 67% of human HNSCC cases converge onto the NOTCH signaling pathway, making NOTCH inactivation a hallmark of HNSCC.

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Supplementary Material

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Materials and Methods
Figs. S1 to S19
Tables S1 to S7
References (3151)

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Science
Volume 367 | Issue 6483
13 March 2020

Submission history

Received: 20 February 2019
Accepted: 14 February 2020
Published in print: 13 March 2020

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Acknowledgments

We thank all members of our laboratories for helpful comments; Y. Q. Lu, D. Dervovic, and G. Mbamalu for assistance; Z. Y. Lin for mass spectrometry assistance; C. Go and J. D. R. Knight for access to the cell-map resource; The Centre for Phenogenomics and Network Biology Collaborative Centre at LTRI; and D. Durocher, J. Wrana, L. Pelletier, R. Bremner, J. McGlade, and J. Woodgett for critically reading the manuscript. Funding: This work was supported by a project grant to D.S. from the Canadian Institute of Health Research (CIHR 365252) and the Krembil Foundation. D.S. is the recipient of a career development award from HFSP (CDA00080/2015). S.K.L. is the recipient of a Canadian Cancer Society fellowship (BC-F-16#31919). A.C.G. was supported by a Terry Fox Research Institute program grant. Author contributions: S.K.L. performed all experiments. K.S. performed Ajuba mouse experiments, immunohistochemistry, and, together with K.T., helped in immunofluorescence experiments. E.L. helped to prepare the viral library. R.T. performed quantitative RT-PCR and CUT&RUN experiments. R.H.O. helped with the random genes library. A.M. performed all bioinformatic analysis. B.R. and A.-C.G. performed and analyzed the mass spectrometry experiments. P.S.-T. helped with the design of the mass spectrometry experiments. R.Q. and T.J.P. performed bioinformatics analysis on human TCGA data. D.S. coordinated the project and, together with S.K.L., designed the experiments and wrote the manuscript. Competing interests: The authors declare no competing interests. Data and materials availability: All mass spectrometry data have been deposited in the MassIVE repository (MSV000083405 and PXD012600). Data for the 192 different BioID baits targeting the major subcellular compartments of a human cell used to control for AJUBA interactome specificity are available at https://humancellmap.org. All code and the manifests used to analyze the human HNSCC TCGA data are available under the R package SchramekLOH v1.0.0 (https://github.com/pughlab/SchramekLOH). All RNA-sequencing and CUT&RUN data are available at the Gene Expression Omnibus (GEO) (GSE140495, GSE140496, and GSE140497). All other data are available in the main text or the supplementary materials.

Authors

Affiliations

Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Krista Schleicher
Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Ahmad Malik
Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Rene Quevedo
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Ellen Langille
Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Katie Teng
Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Robin H. Oh
Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Bhavisha Rathod
Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Ricky Tsai
Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Payman Samavarchi-Tehrani
Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

Funding Information

Terry Fox Research Institute: Terry Fox Research Institute Program Grant

Notes

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Corresponding author. Email: [email protected]

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