TY - JOUR
T1 - Genomic analyses identify molecular subtypes of pancreatic cancer
AU - Australian Pancreatic Cancer Genome Initiative
AU - Bailey, Peter
AU - Chang, David K.
AU - Nones, Katia
AU - Johns, Amber L.
AU - Patch, Ann Marie
AU - Gingras, Marie Claude
AU - Miller, David K.
AU - Christ, Angelika N.
AU - Bruxner, Tim J.C.
AU - Quinn, Michael C.
AU - Nourse, Craig
AU - Murtaugh, L. Charles
AU - Harliwong, Ivon
AU - Idrisoglu, Senel
AU - Manning, Suzanne
AU - Nourbakhsh, Ehsan
AU - Wani, Shivangi
AU - Fink, Lynn
AU - Holmes, Oliver
AU - Chin, Venessa
AU - Anderson, Matthew J.
AU - Kazakoff, Stephen
AU - Leonard, Conrad
AU - Newell, Felicity
AU - Waddell, Nick
AU - Wood, Scott
AU - Xu, Qinying
AU - Wilson, Peter J.
AU - Cloonan, Nicole
AU - Kassahn, Karin S.
AU - Taylor, Darrin
AU - Quek, Kelly
AU - Robertson, Alan
AU - Pantano, Lorena
AU - Mincarelli, Laura
AU - Sanchez, Luis N.
AU - Evers, Lisa
AU - Wu, Jianmin
AU - Pinese, Mark
AU - Cowley, Mark J.
AU - Jones, Marc D.
AU - Colvin, Emily K.
AU - Nagrial, Adnan M.
AU - Humphrey, Emily S.
AU - Chantrill, Lorraine A.
AU - Mawson, Amanda
AU - Humphris, Jeremy
AU - Chou, Angela
AU - Mukhopadhyay, Debabrata
AU - Petersen, Gloria M.
N1 - Funding Information:
Acknowledgements We would like to thank C. Axford, M.-A. Brancato, S. Rowe, M. Thomas, S. Simpson and G. Hammond for central coordination of the Australian Pancreatic Cancer Genome Initiative, data management and quality control; M. Martyn-Smith, L. Braatvedt, H. Tang, V. Papangelis and M. Beilin for biospecimen acquisition; and Deborah Gwynne for support at the Queensland Centre for Medical Genomics. We also thank M. Hodgins, M. Debeljak and D. Trusty for technical assistance at Johns Hopkins University. Funding support was from: National Health and Medical Research Council of Australia (NHMRC; 631701, 535903, 427601); Queensland Government (NIRAP); University of Queensland; Australian Government: Department of Innovation, Industry, Science and Research (DIISR); Australian Cancer Research Foundation (ACRF); Cancer Council NSW: (SRP06-01, SRP11-01. ICGC); Cancer Institute NSW: (10/ECF/2-26; 06/ECF/1-24; 09/CDF/2-40; 07/CDF/1-03; 10/CRF/1-01, 08/RSA/1-15, 07/CDF/1-28, 10/CDF/2-26,10/FRL/2-03, 06/RSA/1-05, 09/RIG/1-02, 10/TPG/1-04, 11/REG/1-10, 11/CDF/3-26); Garvan Institute of Medical Research; Cancer Research UK Glasgow Centre Program, A18076; Avner Nahmani Pancreatic Cancer Research Foundation; R.T. Hall Trust; Petre Foundation; Philip Hemstritch Foundation; Gastroenterological Society of Australia (GESA); American Association for Cancer Research (AACR) Landon Foundation—INNOVATOR Award; Wellcome Trust Senior Investigator Award 103721/Z/14/Z; Cancer Research UK Programme Grant C29717/A17263; Cancer Research UK Programme Grant A12481; Pancreatic Cancer UK; The Howat Foundation; University of Glasgow; European Research Council Starting Grant, 311301, Italian Ministry of University and Research (Cancer Genome Project FIRB RBAP10AHJB), Associazione Italiana Ricerca Cancro (n.12182) , Fondazione Italiana Malattie Pancreas – Ministry of Health (CUP_J33G13000210001), European Community Grant FP7 Cam-Pac, grant agreement number 602783.
Publisher Copyright:
© 2016 Macmillan Publishers Limited. All rights reserved.
PY - 2016/3/3
Y1 - 2016/3/3
N2 - Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63ΔN transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
AB - Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63ΔN transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
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U2 - 10.1038/nature16965
DO - 10.1038/nature16965
M3 - Article
C2 - 26909576
AN - SCOPUS:84960194345
SN - 0028-0836
VL - 531
SP - 47
EP - 52
JO - Nature
JF - Nature
IS - 7592
ER -