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Cis-Compound Mutations are Prevalent in Triple Negative Breast Cancer and Can Drive Tumor Progression

Nao Hiranuma, Jie Liu, Chaozhong Song, Jacob Goldsmith, Michael O. Dorschner, Colin C. Pritchard, Kimberly A. Burton, Elisabeth M. Mahen, Sibel Blau, Francis M. Senecal, Wayne L. Monsky, Stephanie Parker, Stephen C. Schmechel, Stephen K. Allison, Vijayakrishna K. Gadi, Sophie R. Salama, Amie J. Radenbaugh, Mary Goldman, Jill M. Johnsen, Shelly Heimfeld, Vitalina Komashko, Marissa LaMadrid-Hermannsfeldt, Zhijun Duan, Steven C. Benz, Patrick Soon-Shiong, David Haussler, Jingchun Zhu, Walter L. Ruzzo, William S. Noble, C. Anthony Blau
doi: https://doi.org/10.1101/085316
Nao Hiranuma
1Computer Science and Engineering, University of Washington, Seattle, WA
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Jie Liu
2Department of Genome Sciences, University of Washington, Seattle, WA
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Chaozhong Song
3Center for Cancer Innovation, University of Washington, Seattle, WA
4Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA
5Department of Medicine/Hematology, University of Washington, Seattle, WA
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Jacob Goldsmith
5Department of Medicine/Hematology, University of Washington, Seattle, WA
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Michael O. Dorschner
3Center for Cancer Innovation, University of Washington, Seattle, WA
6Department of Pathology University of Washington, Seattle, WA
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Colin C. Pritchard
3Center for Cancer Innovation, University of Washington, Seattle, WA
7Department of Laboratory Medicine, University of Washington, Seattle, WA
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Kimberly A. Burton
3Center for Cancer Innovation, University of Washington, Seattle, WA
4Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA
5Department of Medicine/Hematology, University of Washington, Seattle, WA
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Elisabeth M. Mahen
3Center for Cancer Innovation, University of Washington, Seattle, WA
4Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA
5Department of Medicine/Hematology, University of Washington, Seattle, WA
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Sibel Blau
3Center for Cancer Innovation, University of Washington, Seattle, WA
8Northwest Medical Specialties, Puyallup and Tacoma, WA
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Francis M. Senecal
3Center for Cancer Innovation, University of Washington, Seattle, WA
8Northwest Medical Specialties, Puyallup and Tacoma, WA
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Wayne L. Monsky
9Department of Radiology, University of Washington, Seattle, WA
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Stephanie Parker
8Northwest Medical Specialties, Puyallup and Tacoma, WA
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Stephen C. Schmechel
3Center for Cancer Innovation, University of Washington, Seattle, WA
6Department of Pathology University of Washington, Seattle, WA
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Stephen K. Allison
9Department of Radiology, University of Washington, Seattle, WA
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Vijayakrishna K. Gadi
10Department of Medicine/Oncology, University of Washington, Seattle, WA
11Seattle Cancer Care Alliance, Seattle, WA
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Sophie R. Salama
12University of California at Santa Cruz, Santa Cruz, CA
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Amie J. Radenbaugh
12University of California at Santa Cruz, Santa Cruz, CA
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Mary Goldman
12University of California at Santa Cruz, Santa Cruz, CA
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Jill M. Johnsen
13Bloodworks Northwest, Seattle, WA
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Shelly Heimfeld
14Fred Hutchinson Cancer Research Center Seattle, WA
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Vitalina Komashko
15Trialomics LLC Seattle, WA
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Marissa LaMadrid-Hermannsfeldt
5Department of Medicine/Hematology, University of Washington, Seattle, WA
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Zhijun Duan
3Center for Cancer Innovation, University of Washington, Seattle, WA
4Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA
5Department of Medicine/Hematology, University of Washington, Seattle, WA
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Steven C. Benz
16Nantomics Inc., Culver City, CA
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Patrick Soon-Shiong
16Nantomics Inc., Culver City, CA
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David Haussler
12University of California at Santa Cruz, Santa Cruz, CA
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Jingchun Zhu
3Center for Cancer Innovation, University of Washington, Seattle, WA
12University of California at Santa Cruz, Santa Cruz, CA
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Walter L. Ruzzo
1Computer Science and Engineering, University of Washington, Seattle, WA
2Department of Genome Sciences, University of Washington, Seattle, WA
3Center for Cancer Innovation, University of Washington, Seattle, WA
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William S. Noble
1Computer Science and Engineering, University of Washington, Seattle, WA
2Department of Genome Sciences, University of Washington, Seattle, WA
3Center for Cancer Innovation, University of Washington, Seattle, WA
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C. Anthony Blau
2Department of Genome Sciences, University of Washington, Seattle, WA
3Center for Cancer Innovation, University of Washington, Seattle, WA
4Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA
5Department of Medicine/Hematology, University of Washington, Seattle, WA
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  • For correspondence: tblau@uw.edu
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Abstract

About 16% of breast cancers fall into a clinically aggressive category designated triple negative (TNBC) due to a lack of ERBB2, estrogen receptor and progesterone receptor expression1-3. The mutational spectrum of TNBC has been characterized as part of The Cancer Genome Atlas (TCGA)4; however, snapshots of primary tumors cannot reveal the mechanisms by which TNBCs progress and spread. To address this limitation we initiated the Intensive Trial of OMics in Cancer (ITOMIC)-001, in which patients with metastatic TNBC undergo multiple biopsies over space and time5. Whole exome sequencing (WES) of 67 samples from 11 patients identified 426 genes containing multiple distinct single nucleotide variants (SNVs) within the same sample, instances we term Multiple SNVs affecting the Same Gene and Sample (MSSGS). We find that >90% of MSSGS result from cis-compound mutations (in which both SNVs affect the same allele), that MSSGS comprised of SNVs affecting adjacent nucleotides arise from single mutational events, and that most other MSSGS result from the sequential acquisition of SNVs. Some MSSGS drive cancer progression, as exemplified by a TNBC driven by FGFR2(S252W;Y375C). MSSGS are more prevalent in TNBC than other breast cancer subtypes and occur at higher-than-expected frequencies across TNBC samples within TCGA. MSSGS may denote genes that play as yet unrecognized roles in cancer progression.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 05, 2016.
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Cis-Compound Mutations are Prevalent in Triple Negative Breast Cancer and Can Drive Tumor Progression
Nao Hiranuma, Jie Liu, Chaozhong Song, Jacob Goldsmith, Michael O. Dorschner, Colin C. Pritchard, Kimberly A. Burton, Elisabeth M. Mahen, Sibel Blau, Francis M. Senecal, Wayne L. Monsky, Stephanie Parker, Stephen C. Schmechel, Stephen K. Allison, Vijayakrishna K. Gadi, Sophie R. Salama, Amie J. Radenbaugh, Mary Goldman, Jill M. Johnsen, Shelly Heimfeld, Vitalina Komashko, Marissa LaMadrid-Hermannsfeldt, Zhijun Duan, Steven C. Benz, Patrick Soon-Shiong, David Haussler, Jingchun Zhu, Walter L. Ruzzo, William S. Noble, C. Anthony Blau
bioRxiv 085316; doi: https://doi.org/10.1101/085316
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Cis-Compound Mutations are Prevalent in Triple Negative Breast Cancer and Can Drive Tumor Progression
Nao Hiranuma, Jie Liu, Chaozhong Song, Jacob Goldsmith, Michael O. Dorschner, Colin C. Pritchard, Kimberly A. Burton, Elisabeth M. Mahen, Sibel Blau, Francis M. Senecal, Wayne L. Monsky, Stephanie Parker, Stephen C. Schmechel, Stephen K. Allison, Vijayakrishna K. Gadi, Sophie R. Salama, Amie J. Radenbaugh, Mary Goldman, Jill M. Johnsen, Shelly Heimfeld, Vitalina Komashko, Marissa LaMadrid-Hermannsfeldt, Zhijun Duan, Steven C. Benz, Patrick Soon-Shiong, David Haussler, Jingchun Zhu, Walter L. Ruzzo, William S. Noble, C. Anthony Blau
bioRxiv 085316; doi: https://doi.org/10.1101/085316

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