Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution

Michelle Chan-Seng-Yue, Jaeseung C. Kim, Gavin W. Wilson, Karen Ng, Eugenia Flores Figueroa, Grainne M. O’Kane, Ashton A. Connor, Robert E. Denroche, Robert C. Grant, Jessica McLeod, Julie M. Wilson, Gun Ho Jang, Amy Zhang, Anna Dodd, Sheng Ben Liang, Ayelet Borgida, Dianne Chadwick, Sangeetha Kalimuthu, Ilinca Lungu, John M.S. BartlettPaul M. Krzyzanowski, Vandana Sandhu, Hervé Tiriac, Fieke E.M. Froeling, Joanna M. Karasinska, James T. Topham, Daniel J. Renouf, David F. Schaeffer, Steven J.M. Jones, Marco A. Marra, Janessa Laskin, Runjan Chetty, Lincoln D. Stein, George Zogopoulos, Benjamin Haibe-Kains, Peter J. Campbell, David A. Tuveson, Jennifer J. Knox, Sandra E. Fischer, Steven Gallinger, Faiyaz Notta

Research output: Contribution to journalArticlepeer-review

209 Scopus citations

Abstract

Pancreatic adenocarcinoma presents as a spectrum of a highly aggressive disease in patients. The basis of this disease heterogeneity has proved difficult to resolve due to poor tumor cellularity and extensive genomic instability. To address this, a dataset of whole genomes and transcriptomes was generated from purified epithelium of primary and metastatic tumors. Transcriptome analysis demonstrated that molecular subtypes are a product of a gene expression continuum driven by a mixture of intratumoral subpopulations, which was confirmed by single-cell analysis. Integrated whole-genome analysis uncovered that molecular subtypes are linked to specific copy number aberrations in genes such as mutant KRAS and GATA6. By mapping tumor genetic histories, tetraploidization emerged as a key mutational process behind these events. Taken together, these data support the premise that the constellation of genomic aberrations in the tumor gives rise to the molecular subtype, and that disease heterogeneity is due to ongoing genomic instability during progression.

Original languageEnglish (US)
Pages (from-to)231-240
Number of pages10
JournalNature Genetics
Volume52
Issue number2
DOIs
StatePublished - Feb 1 2020

ASJC Scopus subject areas

  • Genetics

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