Genomic analyses identify molecular subtypes of pancreatic cancer

Peter Bailey; David K Chang; Katia Nones; Amber L Johns; Ann-Marie Patch; Marie-Claude Gingras; David K Miller; Angelika N Christ; Tim J C Bruxner; Michael C Quinn; Craig Nourse; L Charles Murtaugh; Ivon Harliwong; Senel Idrisoglu; Suzanne Manning; Ehsan Nourbakhsh; Shivangi Wani; Lynn Fink; Oliver Holmes; Venessa Chin; Matthew J Anderson; Stephen Kazakoff; Conrad Leonard; Felicity Newell; Nick Waddell; Scott Wood; Qinying Xu; Peter J Wilson; Nicole Cloonan; Karin S Kassahn; Darrin Taylor; Kelly Quek; Alan Robertson; Lorena Pantano; Laura Mincarelli; Luis N Sanchez; Lisa Evers; Jianmin Wu; Mark Pinese; Mark J Cowley; Marc D Jones; Emily K Colvin; Adnan M Nagrial; Emily S Humphrey; Lorraine A Chantrill; Amanda Mawson; Jeremy Humphris; Angela Chou; Marina Pajic; Christopher J Scarlett; Andreia V Pinho; Marc Giry-Laterriere; Ilse Rooman; Jaswinder S Samra; James G Kench; Jessica A Lovell; Neil D Merrett; Christopher W Toon; Krishna Epari; Nam Q Nguyen; Andrew Barbour; Nikolajs Zeps; Kim Moran-Jones; Nigel B Jamieson; Janet S Graham; Fraser Duthie; Karin Oien; Jane Hair; Robert Grützmann; Anirban Maitra; Christine A Iacobuzio-Donahue; Christopher L Wolfgang; Richard A Morgan; Rita T Lawlor; Vincenzo Corbo; Claudio Bassi; Borislav Rusev; Paola Capelli; Roberto Salvia; Giampaolo Tortora; Debabrata Mukhopadhyay; Gloria M Petersen; Australian Pancreatic Cancer Genome Initiative; Donna M Munzy; William E Fisher; Saadia A Karim; James R Eshleman; Ralph H Hruban; Christian Pilarsky; Jennifer P Morton; Owen J Sansom; Aldo Scarpa; Elizabeth A Musgrove; Ulla-Maja Hagbo Bailey; Oliver Hofmann; Robert L Sutherland; David A Wheeler; Anthony J Gill; Richard A Gibbs; John V Pearson; Nicola Waddell; Andrew V Biankin; Sean M Grimmond

doi:10.1038/nature16965

Genomic analyses identify molecular subtypes of pancreatic cancer

Nature. 2016 Mar 3;531(7592):47-52. doi: 10.1038/nature16965. Epub 2016 Feb 24.

Authors

Peter Bailey^{1

2}, David K Chang^{2

3

4

5}, Katia Nones^{1

6}, Amber L Johns³, Ann-Marie Patch^{1

6}, Marie-Claude Gingras^{7

8

9}, David K Miller^{1

3}, Angelika N Christ¹, Tim J C Bruxner¹, Michael C Quinn^{1

6}, Craig Nourse^{1

2}, L Charles Murtaugh¹⁰, Ivon Harliwong¹, Senel Idrisoglu¹, Suzanne Manning¹, Ehsan Nourbakhsh¹, Shivangi Wani^{1

6}, Lynn Fink¹, Oliver Holmes^{1

6}, Venessa Chin³, Matthew J Anderson¹, Stephen Kazakoff^{1

6}, Conrad Leonard^{1

6}, Felicity Newell¹, Nick Waddell¹, Scott Wood^{1

6}, Qinying Xu^{1

6}, Peter J Wilson¹, Nicole Cloonan^{1

6}, Karin S Kassahn^{1

11

12}, Darrin Taylor¹, Kelly Quek¹, Alan Robertson¹, Lorena Pantano¹³, Laura Mincarelli², Luis N Sanchez², Lisa Evers², Jianmin Wu³, Mark Pinese³, Mark J Cowley³, Marc D Jones^{2

3}, Emily K Colvin³, Adnan M Nagrial³, Emily S Humphrey³, Lorraine A Chantrill^{3

14}, Amanda Mawson³, Jeremy Humphris³, Angela Chou^{3

15}, Marina Pajic^{3

16}, Christopher J Scarlett^{3

17}, Andreia V Pinho³, Marc Giry-Laterriere³, Ilse Rooman³, Jaswinder S Samra^{18

19}, James G Kench^{3

19

20}, Jessica A Lovell³, Neil D Merrett^{5

21}, Christopher W Toon³, Krishna Epari²², Nam Q Nguyen²³, Andrew Barbour²⁴, Nikolajs Zeps²⁵, Kim Moran-Jones², Nigel B Jamieson^{2

26

27}, Janet S Graham^{2

28}, Fraser Duthie²⁹, Karin Oien^{3

29}, Jane Hair³⁰, Robert Grützmann³¹, Anirban Maitra³², Christine A Iacobuzio-Donahue³³, Christopher L Wolfgang^{34

35}, Richard A Morgan³⁴, Rita T Lawlor^{36

37}, Vincenzo Corbo³⁶, Claudio Bassi³⁸, Borislav Rusev³⁶, Paola Capelli³⁷, Roberto Salvia³⁸, Giampaolo Tortora³⁹, Debabrata Mukhopadhyay⁴⁰, Gloria M Petersen⁴⁰; Australian Pancreatic Cancer Genome Initiative; Donna M Munzy^{7

8}, William E Fisher⁴¹, Saadia A Karim⁴², James R Eshleman³⁴, Ralph H Hruban³⁴, Christian Pilarsky³¹, Jennifer P Morton⁴², Owen J Sansom^{42

43}, Aldo Scarpa^{36

37}, Elizabeth A Musgrove², Ulla-Maja Hagbo Bailey², Oliver Hofmann^{2

13}, Robert L Sutherland³, David A Wheeler^{7

8}, Anthony J Gill^{3

19}, Richard A Gibbs^{7

8}, John V Pearson^{1

6}, Nicola Waddell^{1

6}, Andrew V Biankin^{2

3

4

5

27}, Sean M Grimmond^{1

2

44}

Collaborators

Australian Pancreatic Cancer Genome Initiative:
Andrew V Biankin, Amber L Johns, Catherine J Axford, Amanda Mawson, David K Chang, Christopher J Scarlett, Mary-Anne L Brancato, Skye H Simpson, Mona Martyn-Smith, Lorraine A Chantrill, Venessa T Chin, Angela Chou, Mark J Cowley, Jeremy L Humphris, R Scott Mead, Adnan M Nagrial, Marina Pajic, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Clare Watson, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V Pinho, Marc Giry-Laterriere, Roger J Daly, Elizabeth A Musgrove, Robert L Sutherland, Sean M Grimmond, Nicola Waddell, Karin S Kassahn, David K Miller, Peter J Wilson, Ann-Marie Patch, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Craig Nourse, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Christina Xu, Katia Nones, J Lynn Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, John V Pearson, Peter Bailey, Michael Quinn, Shivashankar Nagaraj, Stephen Kazakoff, Nick Waddell, Keerthana Krisnan, Kelly Quek, David Wood, Jaswinder S Samra, Anthony J Gill, Nick Pavlakis, Alex Guminski, Christopher Toon, Ray Asghari, Neil D Merrett, Darren Pavey, Amitabha Das, Peter H Cosman, Kasim Ismail, Chelsie O'Connnor, Vincent W Lam, Duncan McLeod, Henry C Pleass, Arthur Richardson, Virginia James, James G Kench, Caroline L Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, James Gallagher, Michael Texler, Cindy Forest, Andrew Laycock, Krishna P Epari, Mo Ballal, David R Fletcher, Sanjay Mukhedkar, Charles Gairdner, Nigel A Spry, Bastiaan DeBoer, Ming Chai, Nikolajs Zeps, Maria Beilin, Kynan Feeney, Nan Q Nguyen, Andrew R Ruszkiewicz, Chris Worthley, Chuan P Tan, John Chen, Mark E Brooke-Smith, Virginia Papangelis, Henry Tang, Andrew P Barbour, Andrew D Clouston, Patrick Martin, Thomas J O'Rourke, Jonathan W Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi, Mehrdad Nikfarjam, Angela Mountain, Aldo Scarpa, Rita T Lawlor, Nicola Sperandio, Giada Bonizzato, Sonia Grimaldi, Cinzia Cantù, Paola Merlini, Giona Turri, Antonio Pea, Corrado Pedrazzani, Andrea Ruzzenente, Stefano Gobbo, Guido Martignoni, Roberto Girelli, Andrew V Biankin, Sean M Grimmond, David K Chang, Elizabeth A Musgrove, Marc D Jones, Craig Nourse, Nigel B Jamieson, Janet S Graham, Andrew V Biankin, David K Chang, Marc D Jones, Nigel B Jamieson, Janet S Graham

Affiliations

¹ Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
² Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
³ The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia.
⁴ Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia.
⁵ South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia.
⁶ QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
⁷ Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
⁸ Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA.
⁹ Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
¹⁰ Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA.
¹¹ Genetic and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia.
¹² School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia.
¹³ Harvard Chan Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
¹⁴ Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales 2560, Australia.
¹⁵ Department of Pathology. SydPath, St Vincent's Hospital, Sydney, NSW 2010, Australia.
¹⁶ St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2052, Australia.
¹⁷ School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia.
¹⁸ Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia.
¹⁹ University of Sydney, Sydney, New South Wales 2006, Australia.
²⁰ Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown New South Wales 2050, Australia.
²¹ School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, Australia.
²² Fiona Stanley Hospital, Robin Warren Drive, Murdoch, Western Australia 6150, Australia.
²³ Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia.
²⁴ Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia.
²⁵ School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia and St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia.
²⁶ Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK.
²⁷ West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK.
²⁸ Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK.
²⁹ Department of Pathology, Southern General Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK.
³⁰ GGC Bio-repository, Pathology Department, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TY, UK.
³¹ Department of Surgery, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
³² Departments of Pathology and Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston Texas 77030, USA.
³³ The David M. Rubenstein Pancreatic Cancer Research Center and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
³⁴ Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
³⁵ Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
³⁶ ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy.
³⁷ Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy.
³⁸ Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy.
³⁹ Department of Medical Oncology, Comprehensive Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy.
⁴⁰ Mayo Clinic, Rochester, Minnesota 55905, USA.
⁴¹ Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
⁴² Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
⁴³ Institute for Cancer Science, University of Glasgow, Glasgow G12 8QQ, UK.
⁴⁴ University of Melbourne, Parkville, Victoria 3010, Australia.

PMID: 26909576
DOI: 10.1038/nature16965

Abstract

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 TP63∆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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors / genetics
Carcinoma, Pancreatic Ductal / classification
Carcinoma, Pancreatic Ductal / genetics
Carcinoma, Pancreatic Ductal / immunology
Carcinoma, Pancreatic Ductal / metabolism
Carcinoma, Pancreatic Ductal / pathology
Cell Line, Tumor
DNA Methylation
DNA-Binding Proteins / genetics
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Genes, Neoplasm / genetics*
Genome, Human / genetics*
Genomics*
Hepatocyte Nuclear Factor 3-beta / genetics
Hepatocyte Nuclear Factor 3-gamma / genetics
Histone Demethylases / genetics
Homeobox Protein Nkx-2.2
Homeodomain Proteins / genetics
Humans
Mice
Mutation / genetics*
Nuclear Proteins / genetics
Pancreatic Neoplasms / classification*
Pancreatic Neoplasms / genetics*
Pancreatic Neoplasms / immunology
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
Prognosis
Receptors, Cytoplasmic and Nuclear / genetics
Survival Analysis
Trans-Activators / genetics
Transcription Factors / genetics
Transcription, Genetic
Transcriptome
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Proteins / genetics
Zebrafish Proteins

Substances

Basic Helix-Loop-Helix Transcription Factors
DNA-Binding Proteins
FOXA2 protein, human
FOXA3 protein, human
Homeobox Protein Nkx-2.2
Homeodomain Proteins
MNX1 protein, human
NEUROD1 protein, human
NKX2-2 protein, human
NR5A2 protein, human
Nkx2-2 protein, mouse
Nuclear Proteins
RBPJL protein, human
Receptors, Cytoplasmic and Nuclear
TP53 protein, human
TP63 protein, human
Trans-Activators
Transcription Factors
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Zebrafish Proteins
nkx2.2b protein, zebrafish
pancreatic and duodenal homeobox 1 protein
Hepatocyte Nuclear Factor 3-gamma
Hepatocyte Nuclear Factor 3-beta
Histone Demethylases
KDM6A protein, human

Associated data

GEO/GSE36924
GEO/GSE49149

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding