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Tumor mutational landscape is a record of the pre-malignant state

Kirsten Kübler, Rosa Karlić, Nicholas J. Haradhvala, Kyungsik Ha, Jaegil Kim, Maja Kuzman, Wei Jiao, Sitanshu Gakkhar, Kent W. Mouw, Lior Z. Braunstein, Olivier Elemento, Andrew V. Biankin, Ilse Rooman, Mendy Miller, Wouter R. Karthaus, Christopher D. Nogiec, Edouard Juvenson, Edward Curry, Mari Mino- Kenudson, Leif W. Ellisen, Robert Brown, Alexander Gusev, Cristian Tomasetti, Martijn P. Lolkema, Neeltje Steeghs, Carla van Herpen, Hong-Gee Kim, Hwajin Lee, Kristian Vlahoviček, Bradley E. Bernstein, Charles L. Sawyers, Katherine A. Hoadley, Edwin Cuppen, Amnon Koren, Peter F. Arndt, David N. Louis, Lincoln D. Stein, William D. Foulkes, Paz Polak, Gad Getz, on behalf of the PCAWG Pathology and Clinical Correlates Working Group, and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
doi: https://doi.org/10.1101/517565
Kirsten Kübler
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
2Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts, USA
3Harvard Medical School, Boston, Massachusetts, USA
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Rosa Karlić
4Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia
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Nicholas J. Haradhvala
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
2Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts, USA
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Kyungsik Ha
5Biomedical Knowledge Engineering Laboratory, Seoul National University, Seoul, South Korea
6Interdisciplinary Program of Medical Informatics, College of Medicine, Seoul National University, Seoul, South Korea
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Jaegil Kim
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Maja Kuzman
4Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia
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Wei Jiao
7Adaptive Oncology Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
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Sitanshu Gakkhar
8Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
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Kent W. Mouw
3Harvard Medical School, Boston, Massachusetts, USA
9Department of Radiation Oncology, Brigham & Women’s Hospital and Dana Farber Cancer Institute, Boston, Massachusetts, USA
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Lior Z. Braunstein
10Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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Olivier Elemento
11Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA
12Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medical College, New York, New York, USA
13Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, New York, USA
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Andrew V. Biankin
14Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, UK
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Ilse Rooman
15Laboratory of Medical and Molecular Oncology, Oncology Research Center, Vrije Universiteit Brussel, Laarbeeklaan, Brussels, Belgium
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Mendy Miller
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Wouter R. Karthaus
16Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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Christopher D. Nogiec
17Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Edouard Juvenson
18McGill University Health Centre, McGill University, Montreal, Quebec
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Edward Curry
19Department Surgery and Cancer, Imperial College London, London, United Kingdom
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Mari Mino- Kenudson
3Harvard Medical School, Boston, Massachusetts, USA
20Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
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Leif W. Ellisen
2Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts, USA
3Harvard Medical School, Boston, Massachusetts, USA
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Robert Brown
19Department Surgery and Cancer, Imperial College London, London, United Kingdom
21Institute of Cancer Research, Sutton, United Kingdom
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Alexander Gusev
3Harvard Medical School, Boston, Massachusetts, USA
22Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
23Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
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Cristian Tomasetti
24Sidney Kimmel Cancer Center at Johns Hopkins, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
25Division of Biostatistics and Bioinformatics, Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
26Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
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Martijn P. Lolkema
27Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
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Neeltje Steeghs
28Department of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, The Netherlands
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Carla van Herpen
29Radboud University Medical Center, Nijmegen, the Netherlands
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Hong-Gee Kim
5Biomedical Knowledge Engineering Laboratory, Seoul National University, Seoul, South Korea
30Dental Research Institute, School of Dentistry, Seoul National University, Seoul, South Korea
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Hwajin Lee
5Biomedical Knowledge Engineering Laboratory, Seoul National University, Seoul, South Korea
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Kristian Vlahoviček
4Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia
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Bradley E. Bernstein
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
3Harvard Medical School, Boston, Massachusetts, USA
20Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
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Charles L. Sawyers
16Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
31Howard Hughes Medical Institute, Chevy Chase, Maryland, USA
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Katherine A. Hoadley
32Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Edwin Cuppen
33Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
34Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands
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Amnon Koren
35Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA
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Peter F. Arndt
36Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestr. 63/73, 14195 Berlin, Germany
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David N. Louis
2Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts, USA
3Harvard Medical School, Boston, Massachusetts, USA
20Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
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Lincoln D. Stein
7Adaptive Oncology Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
37Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
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William D. Foulkes
38Department of Human Genetics, McGill University, Montreal, Quebec, Canada
39Lady Davis Institute for Medical Research and Research Institute McGill University Health Centre, McGill University, Montreal, Quebec, Canada
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Paz Polak
17Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
40Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
41Department of Pathology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
42Department of Medicine, Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Gad Getz
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
2Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts, USA
3Harvard Medical School, Boston, Massachusetts, USA
20Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
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  • For correspondence: gadgetz@broadinstitute.org
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ABSTRACT

Chromatin structure has a major influence on the cell-specific density of somatic mutations along the cancer genome. Here, we present a pan-cancer study in which we searched for the putative cancer cell-of-origin of 2,550 whole genomes, representing 32 cancer types by matching their mutational landscape to the regional patterns of chromatin modifications ascertained in 104 normal tissue types. We found that, in almost all cancer types, the cell-of-origin can be predicted solely from their DNA sequences. Our analysis validated the hypothesis that high-grade serous ovarian cancer originates in the fallopian tube and identified distinct origins of breast cancer subtypes. We also demonstrated that the technique is equally capable of identifying the cell-of-origin for a series of 2,044 metastatic samples from 22 of the tumor types available as primaries. Moreover, cancer drivers, whether inherited or acquired, reside in active chromatin regions in the respective cell-of-origin. Taken together, our findings highlight that many somatic mutations accumulate while the chromatin structure of the cell-of-origin is maintained and that this historical record, captured in the DNA, can be used to identify the often elusive cancer cell-of-origin.

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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-NC-ND 4.0 International license.
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Posted January 11, 2019.
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Tumor mutational landscape is a record of the pre-malignant state
Kirsten Kübler, Rosa Karlić, Nicholas J. Haradhvala, Kyungsik Ha, Jaegil Kim, Maja Kuzman, Wei Jiao, Sitanshu Gakkhar, Kent W. Mouw, Lior Z. Braunstein, Olivier Elemento, Andrew V. Biankin, Ilse Rooman, Mendy Miller, Wouter R. Karthaus, Christopher D. Nogiec, Edouard Juvenson, Edward Curry, Mari Mino- Kenudson, Leif W. Ellisen, Robert Brown, Alexander Gusev, Cristian Tomasetti, Martijn P. Lolkema, Neeltje Steeghs, Carla van Herpen, Hong-Gee Kim, Hwajin Lee, Kristian Vlahoviček, Bradley E. Bernstein, Charles L. Sawyers, Katherine A. Hoadley, Edwin Cuppen, Amnon Koren, Peter F. Arndt, David N. Louis, Lincoln D. Stein, William D. Foulkes, Paz Polak, Gad Getz, on behalf of the PCAWG Pathology and Clinical Correlates Working Group, and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
bioRxiv 517565; doi: https://doi.org/10.1101/517565
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Tumor mutational landscape is a record of the pre-malignant state
Kirsten Kübler, Rosa Karlić, Nicholas J. Haradhvala, Kyungsik Ha, Jaegil Kim, Maja Kuzman, Wei Jiao, Sitanshu Gakkhar, Kent W. Mouw, Lior Z. Braunstein, Olivier Elemento, Andrew V. Biankin, Ilse Rooman, Mendy Miller, Wouter R. Karthaus, Christopher D. Nogiec, Edouard Juvenson, Edward Curry, Mari Mino- Kenudson, Leif W. Ellisen, Robert Brown, Alexander Gusev, Cristian Tomasetti, Martijn P. Lolkema, Neeltje Steeghs, Carla van Herpen, Hong-Gee Kim, Hwajin Lee, Kristian Vlahoviček, Bradley E. Bernstein, Charles L. Sawyers, Katherine A. Hoadley, Edwin Cuppen, Amnon Koren, Peter F. Arndt, David N. Louis, Lincoln D. Stein, William D. Foulkes, Paz Polak, Gad Getz, on behalf of the PCAWG Pathology and Clinical Correlates Working Group, and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
bioRxiv 517565; doi: https://doi.org/10.1101/517565

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