Journal
NATURE
Volume 531, Issue 7592, Pages 47-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature16965
Keywords
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Funding
- 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, A12481]
- Pancreatic Cancer UK
- 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 [12182]
- Fondazione Italiana Malattie Pancreas - Ministry of Health [CUP_J33G13000210001]
- European Community Grant FP7 Cam-Pac [602783]
- Wellcome Trust [103721/Z/14/Z] Funding Source: Wellcome Trust
- Academy of Medical Sciences (AMS) [AMS-SGCL9-Jamieson] Funding Source: researchfish
- Cancer Research UK [22533, 12946, 11650, 17263] Funding Source: researchfish
- Cancer Research UK
- Versus Arthritis [21139] Funding Source: researchfish
- Medical Research Council [MR/N005813/1] Funding Source: researchfish
- Pancreatic Cancer UK [RIF2015_A06_Jamieson] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [20409] Funding Source: researchfish
- Wellcome Trust [103721/Z/14/Z] Funding Source: researchfish
- MRC [MR/N005813/1] Funding Source: UKRI
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Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-beta, 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 TP63 Delta N 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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