@article{8d00bf598815437a9dfdd1f810591ec0,
title = "Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution",
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.",
author = "Michelle Chan-Seng-Yue and Kim, {Jaeseung C.} and Wilson, {Gavin W.} and Karen Ng and Figueroa, {Eugenia Flores} and O{\textquoteright}Kane, {Grainne M.} and Connor, {Ashton A.} and Denroche, {Robert E.} and Grant, {Robert C.} and Jessica McLeod and Wilson, {Julie M.} and Jang, {Gun Ho} and Amy Zhang and Anna Dodd and Liang, {Sheng Ben} and Ayelet Borgida and Dianne Chadwick and Sangeetha Kalimuthu and Ilinca Lungu and Bartlett, {John M.S.} and Krzyzanowski, {Paul M.} and Vandana Sandhu and Herv{\'e} Tiriac and Froeling, {Fieke E.M.} and Karasinska, {Joanna M.} and Topham, {James T.} and Renouf, {Daniel J.} and Schaeffer, {David F.} and Jones, {Steven J.M.} and Marra, {Marco A.} and Janessa Laskin and Runjan Chetty and Stein, {Lincoln D.} and George Zogopoulos and Benjamin Haibe-Kains and Campbell, {Peter J.} and Tuveson, {David A.} and Knox, {Jennifer J.} and Fischer, {Sandra E.} and Steven Gallinger and Faiyaz Notta",
note = "Funding Information: We thank all members of the Notta Laboratory and PanCuRx program at the Ontario Institute for Cancer Research (OICR) for their critical review of the manuscript, and the Genomics Technology Program at OICR for technical support. We also thank F. Real and B. Stanger for intellectual input and critical discussions regarding the manuscript. We also acknowledge the participation of patients and their families, and the POG and PanGen teams. This study was conducted with the support of OICR (PanCuRx Translational Research Initiative) through funding provided by the Government of Ontario, the Wallace McCain Centre for Pancreatic Cancer supported by the Princess Margaret Cancer Foundation, the Terry Fox Research Institute, the Canadian Cancer Society Research Institute and the Pancreatic Cancer Canada Foundation. The study was also supported by charitable donations from the Canadian Friends of the Hebrew University (A. U. Soyka). S.G. is the recipient of an Investigator Award from OICR. G.Z. is a clinical research scholar of the Fonds de Recherche en Sant{\'e} du Qu{\'e}bec. F.N. is supported by the Gattuso-Slaight Personalized Cancer Medicine Fund, funding from the OICR, the Canadian Institutes of Health Research (no. 388785) and the Cancer Research Society (no. 23383). G.Z. is a Clinician-Scientist of the Fonds de la Recherche en Sant{\'e} du Qu{\'e}bec. P.J.C. is a Wellcome Trust Senior Clinical Fellow and L.D.S. and S.G. are recipients of Senior or Clinician-Scientist Awards from OICR. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = feb,
day = "1",
doi = "10.1038/s41588-019-0566-9",
language = "English (US)",
volume = "52",
pages = "231--240",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "2",
}