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Title: A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns

Abstract

Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirdsmore » of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.« less

Authors:
 [1];  [1];  [1];  [2];  [1];  [1];  [1];  [3];  [1];  [4];  [5];  [6];  [1];  [7];  [1];  [3];  [8];  [9];  [1];  [7] more »;  [1];  [1];  [1];  [1];  [10];  [11];  [1];  [1];  [1];  [12];  [11];  [1];  [13];  [1];  [1];  [14];  [1];  [15];  [16];  [17];  [18];  [4];  [9];  [9];  [19];  [20] « less
+ Show Author Affiliations
  1. Ontario Inst. for Cancer Research, Toronto, ON (Canada)
  2. Wellcome Trust Sanger Inst., Hinxton (United Kingdom)
  3. Univ. Health Network, Toronto, ON (Canada). UHN Program in BioSpecimen Sciences, Dept. of Pathology
  4. Ontario Inst. for Cancer Research, Toronto, ON (Canada); Univ. of Toronto, ON (Canada). Dept. of Medical Biophysics
  5. Univ. of Toronto, ON (Canada). Dept. of Medical Biophysics; Univ. of Toronto, ON (Canada). Lab.Medicine and Pathobiology
  6. Ontario Inst. for Cancer Research, Toronto, ON (Canada); Univ. of Toronto, ON (Canada). Dept. of Computer Science
  7. Nebraska Medical Center, Omaha, NE (United States). Eppley Inst. for Research in Cancer
  8. Ontario Inst. for Cancer Research, Toronto, ON (Canada); Univ. Health Network, Toronto, ON (Canada). UHN Program in BioSpecimen Sciences, Dept. of Pathology
  9. Ontario Inst. for Cancer Research, Toronto, ON (Canada); Univ. of Toronto, ON (Canada). Molecular Genetics
  10. Sunnybrook Health Sciences Centre, Toronto, ON (Canada). Odette Cancer Centre, Division of Surgical Oncology
  11. University Health Network (UHN), Toronto, ON (Canada). Princess Margaret Cancer Centre
  12. Mayo Clinic, Rochester, MN (United States). Dept. of Health Sciences Research
  13. Univ. of Toronto, ON (Canada). Dept. of Medical Biophysics; University Health Network (UHN), Toronto, ON (Canada). Princess Margaret Cancer Centre
  14. McGill Univ. Health Centre, Montreal, QC (Canada). Research Inst.
  15. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  16. Spanish National Cancer Research Centre (CNIO), Madrid (Spain). Epithelial Carcinogenesis Group; Univ. Pompeu Fabra, Barcelona (Spain)
  17. Mount Sinai Hospital, Toronto, ON (Canada). Lunenfeld-Tanenbaum Research Inst.; Univ. Health Network, Toronto, ON (Canada). Dept. of Surgery
  18. Univ. Health Network, Toronto, ON (Canada). UHN Program in BioSpecimen Sciences, Dept. of Pathology; University Health Network (UHN), Toronto, ON (Canada). Princess Margaret Cancer Centre
  19. Wellcome Trust Sanger Inst., Hinxton (United Kingdom); Univ. of Cambridge (United Kingdom). Dept. of Hematology
  20. Ontario Inst. for Cancer Research, Toronto, ON (Canada); Mount Sinai Hospital, Toronto, ON (Canada). Lunenfeld-Tanenbaum Research Inst.; Univ. Health Network, Toronto, ON (Canada). Dept. of Surgery
Publication Date:
Research Org.:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE Laboratory Directed Research and Development (LDRD) Program; National Cancer Institute (NCI)
OSTI Identifier:
1458939
Report Number(s):
LA-UR-16-22279
Journal ID: ISSN 0028-0836
Grant/Contract Number:  
AC52-06NA25396; P50 CA102701; R01 CA97075
Resource Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 538; Journal Issue: 7625; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science

Citation Formats

Notta, Faiyaz, Chan-Seng-Yue, Michelle, Lemire, Mathieu, Li, Yilong, Wilson, Gavin W., Connor, Ashton A., Denroche, Robert E., Liang, Sheng-Ben, Brown, Andrew M. K., Kim, Jaeseung C., Wang, Tao, Simpson, Jared T., Beck, Timothy, Borgida, Ayelet, Buchner, Nicholas, Chadwick, Dianne, Hafezi-Bakhtiari, Sara, Dick, John E., Heisler, Lawrence, Hollingsworth, Michael A., Ibrahimov, Emin, Jang, Gun Ho, Johns, Jeremy, Jorgensen, Lars G. T., Law, Calvin, Ludkovski, Olga, Lungu, Ilinca, Ng, Karen, Pasternack, Danielle, Petersen, Gloria M., Shlush, Liran I., Timms, Lee, Tsao, Ming-Sound, Wilson, Julie M., Yung, Christina K., Zogopoulos, George, Bartlett, John M. S., Alexandrov, Ludmil B., Real, Francisco X., Cleary, Sean P., Roehrl, Michael H., McPherson, John D., Stein, Lincoln D., Hudson, Thomas J., Campbell, Peter J., and Gallinger, Steven. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. United States: N. p., 2016. Web. doi:10.1038/nature19823.
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Notta, Faiyaz, Chan-Seng-Yue, Michelle, Lemire, Mathieu, Li, Yilong, Wilson, Gavin W., Connor, Ashton A., Denroche, Robert E., Liang, Sheng-Ben, Brown, Andrew M. K., Kim, Jaeseung C., Wang, Tao, Simpson, Jared T., Beck, Timothy, Borgida, Ayelet, Buchner, Nicholas, Chadwick, Dianne, Hafezi-Bakhtiari, Sara, Dick, John E., Heisler, Lawrence, Hollingsworth, Michael A., Ibrahimov, Emin, Jang, Gun Ho, Johns, Jeremy, Jorgensen, Lars G. T., Law, Calvin, Ludkovski, Olga, Lungu, Ilinca, Ng, Karen, Pasternack, Danielle, Petersen, Gloria M., Shlush, Liran I., Timms, Lee, Tsao, Ming-Sound, Wilson, Julie M., Yung, Christina K., Zogopoulos, George, Bartlett, John M. S., Alexandrov, Ludmil B., Real, Francisco X., Cleary, Sean P., Roehrl, Michael H., McPherson, John D., Stein, Lincoln D., Hudson, Thomas J., Campbell, Peter J., & Gallinger, Steven. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. United States. https://doi.org/10.1038/nature19823
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Notta, Faiyaz, Chan-Seng-Yue, Michelle, Lemire, Mathieu, Li, Yilong, Wilson, Gavin W., Connor, Ashton A., Denroche, Robert E., Liang, Sheng-Ben, Brown, Andrew M. K., Kim, Jaeseung C., Wang, Tao, Simpson, Jared T., Beck, Timothy, Borgida, Ayelet, Buchner, Nicholas, Chadwick, Dianne, Hafezi-Bakhtiari, Sara, Dick, John E., Heisler, Lawrence, Hollingsworth, Michael A., Ibrahimov, Emin, Jang, Gun Ho, Johns, Jeremy, Jorgensen, Lars G. T., Law, Calvin, Ludkovski, Olga, Lungu, Ilinca, Ng, Karen, Pasternack, Danielle, Petersen, Gloria M., Shlush, Liran I., Timms, Lee, Tsao, Ming-Sound, Wilson, Julie M., Yung, Christina K., Zogopoulos, George, Bartlett, John M. S., Alexandrov, Ludmil B., Real, Francisco X., Cleary, Sean P., Roehrl, Michael H., McPherson, John D., Stein, Lincoln D., Hudson, Thomas J., Campbell, Peter J., and Gallinger, Steven. Wed . "A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns". United States. https://doi.org/10.1038/nature19823. https://www.osti.gov/servlets/purl/1458939.
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@article{osti_1458939,
title = {A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns},
author = {Notta, Faiyaz and Chan-Seng-Yue, Michelle and Lemire, Mathieu and Li, Yilong and Wilson, Gavin W. and Connor, Ashton A. and Denroche, Robert E. and Liang, Sheng-Ben and Brown, Andrew M. K. and Kim, Jaeseung C. and Wang, Tao and Simpson, Jared T. and Beck, Timothy and Borgida, Ayelet and Buchner, Nicholas and Chadwick, Dianne and Hafezi-Bakhtiari, Sara and Dick, John E. and Heisler, Lawrence and Hollingsworth, Michael A. and Ibrahimov, Emin and Jang, Gun Ho and Johns, Jeremy and Jorgensen, Lars G. T. and Law, Calvin and Ludkovski, Olga and Lungu, Ilinca and Ng, Karen and Pasternack, Danielle and Petersen, Gloria M. and Shlush, Liran I. and Timms, Lee and Tsao, Ming-Sound and Wilson, Julie M. and Yung, Christina K. and Zogopoulos, George and Bartlett, John M. S. and Alexandrov, Ludmil B. and Real, Francisco X. and Cleary, Sean P. and Roehrl, Michael H. and McPherson, John D. and Stein, Lincoln D. and Hudson, Thomas J. and Campbell, Peter J. and Gallinger, Steven},
abstractNote = {Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.},
doi = {10.1038/nature19823},
journal = {Nature (London)},
number = 7625,
volume = 538,
place = {United States},
year = {Wed Oct 12 00:00:00 EDT 2016},
month = {Wed Oct 12 00:00:00 EDT 2016}
}
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    • Birnbaum, David Jérémie; Bertucci, François; Finetti, Pascal
    • Cancers, Vol. 11, Issue 4
    • DOI: 10.3390/cancers11040497

    NF-κB/Rel Transcription Factors in Pancreatic Cancer: Focusing on RelA, c-Rel, and RelB
    journal, July 2019

    The Evolving Understanding of the Molecular and Therapeutic Landscape of Pancreatic Ductal Adenocarcinoma
    journal, November 2018

    Meta-Analysis of Cancer Triploidy: Rearrangements of Genome Complements in Male Human Tumors Are Characterized by XXY Karyotypes
    journal, August 2019

    • Vainshelbaum, Ninel M.; Zayakin, Pawel; Kleina, Regina
    • Genes, Vol. 10, Issue 8
    • DOI: 10.3390/genes10080613

    Current Clinical Strategies of Pancreatic Cancer Treatment and Open Molecular Questions
    journal, September 2019

    • Brunner, Maximilian; Wu, Zhiyuan; Krautz, Christian
    • International Journal of Molecular Sciences, Vol. 20, Issue 18
    • DOI: 10.3390/ijms20184543

    Integrated analysis of gene expression and methylation profiles of novel pancreatic cancer cell lines with highly metastatic activity
    journal, March 2019

    Precancerous neoplastic cells can move through the pancreatic ductal system
    journal, September 2018

    Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes.
    text, January 2018

    • Mueller, Sebastian; Engleitner, Thomas; Maresch, Roman
    • Apollo - University of Cambridge Repository
    • DOI: 10.17863/cam.23150

    Whole Genomes Define Concordance of Matched Primary, Xenograft, and Organoid Models of Pancreas Cancer
    journal, December 2017

    • Gendoo, Deena M. A.; Denroche, Robert E.; Zhang, Amy
    • PLOS Computational Biology
    • DOI: 10.1101/209692

    Expression-based analyses indicate a central role for hypoxia in driving tumor plasticity through microenvironment remodeling and chromosomal instability
    journal, May 2018

    • Jing, Anqi; Vizeacoumar, Frederick S.; Parameswaran, Sreejit
    • npj Systems Biology and Applications
    • DOI: 10.1101/333633

    Using State Space Exploration to Determine How Gene Regulatory Networks Constrain Mutation Order in Cancer Evolution
    text, January 2019

    • Clarke, Matthew; Woodhouse, Steven; Piterman, Nir
    • Apollo - University of Cambridge Repository
    • DOI: 10.17863/cam.42094

    Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing.
    journalarticle, January 2020

    • Cortés-Ciriano, Isidro; Lee, Jake June-Koo; Xi, Ruibin
    • Springer Science and Business Media LLC
    • DOI: 10.17863/cam.73656

    Rotten to the Core: Why Micronuclei Rupture
    journal, November 2018

    Mutant Kras Dosage and Chromothripsis: The Right Ingredients for a Pancreatic Cancer Catastrophe
    journal, June 2018

    Genomic comparison of esophageal squamous cell carcinoma and its precursor lesions by multi-region whole-exome sequencing
    journal, September 2017

    Evolution of Barrett’s esophagus through space and time at single-crypt and whole-biopsy levels
    journal, February 2018

    A temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer
    journal, July 2018

    Mutations in BRCA1, BRCA2, and PALB2, and a panel of 50 cancer-associated genes in pancreatic ductal adenocarcinoma
    journal, May 2018

    Deep whole-genome sequencing of 3 cancer cell lines on 2 sequencing platforms
    journal, December 2019

    Expression-based analyses indicate a central role for hypoxia in driving tumor plasticity through microenvironment remodeling and chromosomal instability
    journal, May 2018

    • Jing, Anqi; Vizeacoumar, Frederick S.; Parameswaran, Sreejit
    • npj Systems Biology and Applications
    • DOI: 10.1101/333633

    Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine
    journal, November 2018

    Developing a pan-cancer research autopsy programme
    journal, July 2019

    Spatial UBE2N protein expression indicates genomic instability in colorectal cancers
    journal, July 2019

    Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis
    journal, January 2019

    Chromoanagenesis: a piece of the macroevolution scenario
    journal, January 2020

    Novel agents for pancreatic ductal adenocarcinoma: emerging therapeutics and future directions
    journal, January 2018

    Overexpressed histone acetyltransferase 1 regulates cancer immunity by increasing programmed death-ligand 1 expression in pancreatic cancer
    journal, February 2019

    • Fan, Ping; Zhao, Jingyuan; Meng, Zibo
    • Journal of Experimental & Clinical Cancer Research, Vol. 38, Issue 1
    • DOI: 10.1186/s13046-019-1044-z

    Timing somatic events in the evolution of cancer
    journal, July 2018

    A Markov chain for numerical chromosomal instability in clonally expanding populations
    journal, September 2018

    The Subclonal Architecture of Metastatic Breast Cancer: Results from a Prospective Community-Based Rapid Autopsy Program “CASCADE”
    journal, December 2016

    Behind the Wheel of Epithelial Plasticity in KRAS-Driven Cancers
    journal, October 2019

    Phosphoinositide 3-Kinase Signaling Pathway in Pancreatic Ductal Adenocarcinoma Progression, Pathogenesis, and Therapeutics
    journal, April 2018

    Pancreatic Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells
    journal, November 2017

    Extracellular Influences: Molecular Subclasses and the Microenvironment in Pancreatic Cancer
    journal, January 2018

    • Veenstra, Veronique; Garcia-Garijo, Andrea; van Laarhoven, Hanneke
    • Cancers, Vol. 10, Issue 2
    • DOI: 10.3390/cancers10020034

    Understanding Intratumor Heterogeneity and Evolution in NSCLC and Potential New Therapeutic Approach
    journal, June 2018

    Head and Body/Tail Pancreatic Carcinomas Are Not the Same Tumors
    journal, April 2019

    • Birnbaum, David Jérémie; Bertucci, François; Finetti, Pascal
    • Cancers, Vol. 11, Issue 4
    • DOI: 10.3390/cancers11040497

    The Evolving Understanding of the Molecular and Therapeutic Landscape of Pancreatic Ductal Adenocarcinoma
    journal, November 2018

    Current Clinical Strategies of Pancreatic Cancer Treatment and Open Molecular Questions
    journal, September 2019

    • Brunner, Maximilian; Wu, Zhiyuan; Krautz, Christian
    • International Journal of Molecular Sciences, Vol. 20, Issue 18
    • DOI: 10.3390/ijms20184543
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