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

Ashton A. Connor, Robert E. Denroche, Gun Ho Jang, Mathieu Lemire, Amy Zhang, Michelle Chan-Seng-Yue, Gavin Wilson, Robert C. Grant, Daniele Merico, Ilinca Lungu, John M.S. Bartlett, Dianne Chadwick, Sheng Ben Liang, Jenna Eagles, Faridah Mbabaali, Jessica K. Miller, Paul Krzyzanowski, Heather Armstrong, Xuemei Luo, Lars G.T. JorgensenJoan M. Romero, Prashant Bavi, Sandra E. Fischer, Stefano Serra, Sara Hafezi-Bakhtiari, Derin Caglar, Michael H.A. Roehrl, Sean Cleary, Michael A. Hollingsworth, Gloria M. Petersen, Sarah Thayer, Calvin H.L. Law, Sulaiman Nanji, Talia Golan, Alyssa L. Smith, Ayelet Borgida, Anna Dodd, David Hedley, Bradly G. Wouters, Grainne M. O'Kane, Julie M. Wilson, George Zogopoulos, Faiyaz Notta, Jennifer J. Knox, Steven Gallinger

Research output: Contribution to journalArticle

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)267-282.e7
JournalCancer Cell
Volume35
Issue number2
DOIs
Publication statusPublished - Feb 11 2019

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Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Connor, A. A., Denroche, R. E., Jang, G. H., Lemire, M., Zhang, A., Chan-Seng-Yue, M., ... Gallinger, S. (2019). Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases. Cancer Cell, 35(2), 267-282.e7. https://doi.org/10.1016/j.ccell.2018.12.010