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Precision Medicine and Imaging

Subtype-Discordant Pancreatic Ductal Adenocarcinoma Tumors Show Intermediate Clinical and Molecular Characteristics

James T. Topham, Joanna M. Karasinska, Michael K.C. Lee, Veronika Csizmok, Laura M. Williamson, Gun Ho Jang, Robert E. Denroche, Erica S. Tsang, Steve E. Kalloger, Hui-li Wong, Grainne M. O'Kane, Richard A. Moore, Andrew J. Mungall, Faiyaz Notta, Jonathan M. Loree, Julie M. Wilson, Oliver Bathe, Patricia A. Tang, Rachel Goodwin, Jennifer J. Knox, Steven Gallinger, Janessa Laskin, Marco A. Marra, Steven J.M. Jones, Daniel J. Renouf and David F. Schaeffer
James T. Topham
1Pancreas Centre BC, Vancouver, British Columbia, Canada.
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Joanna M. Karasinska
1Pancreas Centre BC, Vancouver, British Columbia, Canada.
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Michael K.C. Lee
2Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.
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  • ORCID record for Michael K.C. Lee
Veronika Csizmok
3Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada.
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Laura M. Williamson
3Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada.
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Gun Ho Jang
4Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
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Robert E. Denroche
4Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
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Erica S. Tsang
2Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.
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Steve E. Kalloger
1Pancreas Centre BC, Vancouver, British Columbia, Canada.
5Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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Hui-li Wong
2Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.
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Grainne M. O'Kane
4Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
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Richard A. Moore
3Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada.
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Andrew J. Mungall
3Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada.
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Faiyaz Notta
4Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
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Jonathan M. Loree
2Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.
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Julie M. Wilson
4Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
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Oliver Bathe
6The University of Calgary, Calgary, Alberta, Canada.
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Patricia A. Tang
6The University of Calgary, Calgary, Alberta, Canada.
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Rachel Goodwin
7The Ottawa Hospital Cancer Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
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Jennifer J. Knox
8University Health Network, University of Toronto, Toronto, Ontario, Canada.
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Steven Gallinger
4Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
8University Health Network, University of Toronto, Toronto, Ontario, Canada.
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Janessa Laskin
2Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.
3Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada.
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Marco A. Marra
3Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada.
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Steven J.M. Jones
3Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada.
9Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
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Daniel J. Renouf
1Pancreas Centre BC, Vancouver, British Columbia, Canada.
2Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.
10Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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David F. Schaeffer
1Pancreas Centre BC, Vancouver, British Columbia, Canada.
5Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
11Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.
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  • For correspondence: David.Schaeffer@vch.ca
DOI: 10.1158/1078-0432.CCR-20-2831 Published January 2021
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Abstract

Purpose: RNA-sequencing–based subtyping of pancreatic ductal adenocarcinoma (PDAC) has been reported by multiple research groups, each using different methodologies and patient cohorts. “Classical” and “basal-like” PDAC subtypes are associated with survival differences, with basal-like tumors associated with worse prognosis. We amalgamated various PDAC subtyping tools to evaluate the potential of such tools to be reliable in clinical practice.

Experimental Design: Sequencing data for 574 PDAC tumors was obtained from prospective trials and retrospective public databases. Six published PDAC subtyping strategies (Moffitt regression tools, clustering-based Moffitt, Collisson, Bailey, and Karasinska subtypes) were used on each sample, and results were tested for subtype call consistency and association with survival.

Results: Basal-like and classical subtype calls were concordant in 88% of patient samples, and survival outcomes were significantly different (P < 0.05) between prognostic subtypes. Twelve percent of tumors had subtype-discordant calls across the different methods, showing intermediate survival in univariate and multivariate survival analyses. Transcriptional profiles compatible with that of a hybrid subtype signature were observed for subtype-discordant tumors, in which classical and basal-like genes were concomitantly expressed. Subtype-discordant tumors showed intermediate molecular characteristics, including subtyping gene expression (P < 0.0001) and mutant KRAS allelic imbalance (P < 0.001).

Conclusions: Nearly 1 in 6 patients with PDAC have tumors that fail to reliably fall into the classical or basal-like PDAC subtype categories, based on two regression tools aimed toward clinical practice. Rather, these patient tumors show intermediate prognostic and molecular traits. We propose close consideration of the non-binary nature of PDAC subtypes for future incorporation of subtyping into clinical practice.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2021;27:150–7

  • Received July 20, 2020.
  • Revision received September 9, 2020.
  • Accepted October 9, 2020.
  • Published first October 13, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 27 (1)
January 2021
Volume 27, Issue 1
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Subtype-Discordant Pancreatic Ductal Adenocarcinoma Tumors Show Intermediate Clinical and Molecular Characteristics
James T. Topham, Joanna M. Karasinska, Michael K.C. Lee, Veronika Csizmok, Laura M. Williamson, Gun Ho Jang, Robert E. Denroche, Erica S. Tsang, Steve E. Kalloger, Hui-li Wong, Grainne M. O'Kane, Richard A. Moore, Andrew J. Mungall, Faiyaz Notta, Jonathan M. Loree, Julie M. Wilson, Oliver Bathe, Patricia A. Tang, Rachel Goodwin, Jennifer J. Knox, Steven Gallinger, Janessa Laskin, Marco A. Marra, Steven J.M. Jones, Daniel J. Renouf and David F. Schaeffer
Clin Cancer Res January 1 2021 (27) (1) 150-157; DOI: 10.1158/1078-0432.CCR-20-2831

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Subtype-Discordant Pancreatic Ductal Adenocarcinoma Tumors Show Intermediate Clinical and Molecular Characteristics
James T. Topham, Joanna M. Karasinska, Michael K.C. Lee, Veronika Csizmok, Laura M. Williamson, Gun Ho Jang, Robert E. Denroche, Erica S. Tsang, Steve E. Kalloger, Hui-li Wong, Grainne M. O'Kane, Richard A. Moore, Andrew J. Mungall, Faiyaz Notta, Jonathan M. Loree, Julie M. Wilson, Oliver Bathe, Patricia A. Tang, Rachel Goodwin, Jennifer J. Knox, Steven Gallinger, Janessa Laskin, Marco A. Marra, Steven J.M. Jones, Daniel J. Renouf and David F. Schaeffer
Clin Cancer Res January 1 2021 (27) (1) 150-157; DOI: 10.1158/1078-0432.CCR-20-2831
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Clinical Cancer Research
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