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

Faiyaz Notta, Michelle Chan-Seng-Yue, Mathieu Lemire, Yilong Li, Gavin W. Wilson, Ashton A. Connor, Robert E. Denroche, Sheng Ben Liang, Andrew M.K. Brown, Jaeseung C. Kim, Tao Wang, Jared T. Simpson, Timothy Beck, Ayelet Borgida, Nicholas Buchner, Dianne Chadwick, Sara Hafezi-Bakhtiari, John E. Dick, Lawrence Heisler, Michael A. HollingsworthEmin Ibrahimov, Gun Ho Jang, Jeremy Johns, Lars G.T. Jorgensen, Calvin Law, Olga Ludkovski, Ilinca Lungu, Karen Ng, Danielle Pasternack, Gloria M. Petersen, Liran I. Shlush, Lee Timms, Ming Sound Tsao, Julie M. Wilson, Christina K. Yung, George Zogopoulos, John M.S. Bartlett, Ludmil B. Alexandrov, Francisco X. Real, Sean P. Cleary, Michael H. Roehrl, John Douglas Mcpherson, Lincoln D. Stein, Thomas J. Hudson, Peter J. Campbell, Steven Gallinger

Research output: Contribution to journalArticle

156 Citations (Scopus)

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-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.

Original languageEnglish (US)
Pages (from-to)378-382
Number of pages5
JournalNature
Volume538
Issue number7625
DOIs
StatePublished - 2016
Externally publishedYes

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Pancreatic Neoplasms
Neoplasms
Carcinogenesis
DNA Copy Number Variations
Informatics
Carcinoma in Situ
Genome
Mutation
Growth

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Notta, F., Chan-Seng-Yue, M., Lemire, M., Li, Y., Wilson, G. W., Connor, A. A., ... Gallinger, S. (2016). A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature, 538(7625), 378-382. https://doi.org/10.1038/nature19823

A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. / 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 Douglas; Stein, Lincoln D.; Hudson, Thomas J.; Campbell, Peter J.; Gallinger, Steven.

In: Nature, Vol. 538, No. 7625, 2016, p. 378-382.

Research output: Contribution to journalArticle

Notta, F, Chan-Seng-Yue, M, Lemire, M, Li, Y, Wilson, GW, Connor, AA, Denroche, RE, Liang, SB, Brown, AMK, Kim, JC, Wang, T, Simpson, JT, Beck, T, Borgida, A, Buchner, N, Chadwick, D, Hafezi-Bakhtiari, S, Dick, JE, Heisler, L, Hollingsworth, MA, Ibrahimov, E, Jang, GH, Johns, J, Jorgensen, LGT, Law, C, Ludkovski, O, Lungu, I, Ng, K, Pasternack, D, Petersen, GM, Shlush, LI, Timms, L, Tsao, MS, Wilson, JM, Yung, CK, Zogopoulos, G, Bartlett, JMS, Alexandrov, LB, Real, FX, Cleary, SP, Roehrl, MH, Mcpherson, JD, Stein, LD, Hudson, TJ, Campbell, PJ & Gallinger, S 2016, 'A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns', Nature, vol. 538, no. 7625, pp. 378-382. https://doi.org/10.1038/nature19823
Notta F, Chan-Seng-Yue M, Lemire M, Li Y, Wilson GW, Connor AA et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature. 2016;538(7625):378-382. https://doi.org/10.1038/nature19823
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 Douglas ; Stein, Lincoln D. ; Hudson, Thomas J. ; Campbell, Peter J. ; Gallinger, Steven. / A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. In: Nature. 2016 ; Vol. 538, No. 7625. pp. 378-382.
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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-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.",
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