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Cancer Cell. 2019 Feb 11;35(2):267-282.e7. doi: 10.1016/j.ccell.2018.12.010. Epub 2019 Jan 24.

Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases.

Author information

1
PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada.
2
PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
3
PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
4
Deep Genomics, Inc., Toronto, ON M5G 1L7, Canada; The Centre for Applied Genomics (TCAG), The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
5
Diagnostic Development, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
6
UHN Biobank, University Health Network, Toronto, ON M5G 2M9, Canada.
7
Genomics, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
8
Genome Sequence Informatics, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
9
PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON M5G 2M9, Canada.
10
Department of Pathology, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON M5G 2M9, Canada.
11
Department of Pathology, University Health Network, Toronto, ON M5G 2M9, Canada.
12
Department of Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
13
UHN Biobank, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Pathology, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada; Department of Pathology, Memorial Sloan Kettering Cancer Centre, New York, NY 10065, USA.
14
Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA.
15
University of Nebraska Medical Centre, Omaha, NE 68198, USA.
16
Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
17
University of Nebraska Medical Centre, Omaha, NE 68198, USA; Massachusetts General Hospital, Boston, MA 02114, USA.
18
Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada.
19
Department of Surgery, Kingston General Hospital, Kingston, ON K7L 2V7, Canada.
20
Pancreatic Cancer Translational Research Laboratory, Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
21
Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
22
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
23
Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
24
Division of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
25
Division of Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
26
Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Goodman Cancer Research Centre, Montreal, QC H3A 1A3, Canada.
27
PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Division of Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
28
PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada; Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON M5G 2M9, Canada; Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada. Electronic address: steven.gallinger@uhn.ca.

Abstract

We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants. Half of the cases were hypoxic by expression markers, overlapping with molecular subtypes. Paired tumor heterogeneity showed cancer cell migration by Halstedian progression. Multiple PDACs arising synchronously and metachronously in the same pancreas were actually intra-parenchymal metastases, not independent primary tumors. Established clinical co-variates dominated survival analyses, although CCP and hypoxia may inform clinical practice.

KEYWORDS:

RNA sequencing; cell cycle progression; driver genes; hypoxia; metastases; mutational signatures; pancreatic ductal adenocarcinoma; whole-genome sequencing

PMID:
30686769
PMCID:
PMC6398439
[Available on 2020-02-11]
DOI:
10.1016/j.ccell.2018.12.010

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