Abstract

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.

Lakis et al. report novel findings related to the epigenetic landscape of pancreatic neuroendocrine cancer. This relatively large cohort provides functional insights into the epigenetic wiring of pancreatic neuroendocrine tumor sub-types with the potential ability to stratify tumours of different prognosis.

Details

Title
DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association
Author
Lakis Vanessa 1   VIAFID ORCID Logo  ; Lawlor, Rita T 2 ; Newell, Felicity 1   VIAFID ORCID Logo  ; Patch Ann-Marie 1   VIAFID ORCID Logo  ; Mafficini Andrea 2   VIAFID ORCID Logo  ; Sadanandam Anguraj 3   VIAFID ORCID Logo  ; Koufariotis, Lambros T 1 ; Johnston, Rebecca L 1   VIAFID ORCID Logo  ; Conrad, Leonard 1   VIAFID ORCID Logo  ; Wood, Scott 1   VIAFID ORCID Logo  ; Rusev Borislav 2 ; Corbo Vincenzo 4 ; Luchini, Claudio 4   VIAFID ORCID Logo  ; Cingarlini Sara 5 ; Landoni Luca 6   VIAFID ORCID Logo  ; Salvia, Roberto 6 ; Milella, Michele 5 ; Chang, David 7   VIAFID ORCID Logo  ; Bailey, Peter 8 ; Jamieson, Nigel B 7   VIAFID ORCID Logo  ; Duthie Fraser 9 ; Gingras Marie-Claude 10   VIAFID ORCID Logo  ; Muzny, Donna M 11 ; Wheeler, David A 11   VIAFID ORCID Logo  ; Gibbs, Richard A 12 ; Milione Massimo 13 ; Chantrill, Lorraine A 14 ; Timpson, Paul 15 ; Chou, Angela 16 ; Pajic Marina 15 ; Murphy, Angela 15 ; Dwarte Tanya 15 ; Hermann, David 15 ; Vennin Claire 15 ; Cox, Thomas R 15 ; Pereira, Brooke 15 ; Ritchie, Shona 15 ; Reed, Daniel A 15 ; Chambers, Cecilia R 15 ; Metcalf Xanthe 15 ; Nobis, Max 15 ; Mukhopadhyay, Pamela 1 ; Venkateswar, Addala 1 ; Kazakoff, Stephen 1 ; Holmes, Oliver 1 ; Xu Qinying 1 ; Hofmann, Oliver 17 ; Samra, Jaswinder S 18 ; Pavlakis, Nick 18 ; Arena, Jennifer 18 ; High, Hilda A 18 ; Asghari, Ray 19 ; Merrett, Neil D 19 ; Pavey, Darren 19 ; Das Amitabha 19 ; Cosman, Peter H 20 ; Ismail Kasim 20 ; O’Connnor Chelsie 20 ; Stoita Alina 21 ; Williams, David 21 ; Spigellman Allan 21 ; Lam, Vincent W 22 ; McLeod, Duncan 22 ; Kirk, Judy 22 ; Kench, James G 23 ; Grimison, Peter 23 ; Sandroussi Charbel 23 ; Goodwin, Annabel 24 ; Scott, Mead R 25 ; Tucker, Katherine 26 ; Andrews, Lesley 26 ; Texler, Michael 27 ; Forest, Cindy 27 ; Ballal Mo 27 ; Fletcher, David R 27 ; Zeps Nikolajs 28 ; Nguyen, Nan Q 29 ; Ruszkiewicz, Andrew R 29 ; Worthley, Chris 29 ; Chen, John 30 ; Brooke-Smith, Mark E 30 ; Papangelis Virginia 30 ; Clouston, Andrew D 31 ; Barbour, Andrew P 32 ; O’Rourke Thomas J 32 ; Fawcett, Jonathan W 32 ; Slater Kellee 32 ; Hatzifotis, Michael 32 ; Hodgkinson, Peter 32 ; Nikfarjam Mehrdad 33 ; Eshleman, James R 34 ; Hruban, Ralph H 34 ; Wolfgang, Christopher L 34 ; Dixon, Judith 25 ; Scardoni, Maria 4 ; Bassi, Claudio 35 ; Grimaldi, Sonia 2 ; Cantù Cinzia 4 ; Bonizzato Giada 2 ; Bersani, Samantha 36 ; Antonello Davide 37 ; Piredda Liliana 2 ; Sperandio, Nicola 2 ; Barbi Stefano 36 ; Merlini, Paola 2 ; Pederzoli Paolo 38 ; Gill, Anthony J 39 ; Johns, Amber L 15 ; Pearson, John V 1 ; Biankin, Andrew V 25   VIAFID ORCID Logo  ; Grimmond Sean M 17   VIAFID ORCID Logo  ; Waddell, Nicola 40   VIAFID ORCID Logo  ; Nones Katia 1   VIAFID ORCID Logo  ; Scarpa Aldo 41   VIAFID ORCID Logo 

1  QIMR Berghofer Medical Research Institute, Brisbane, Australia (GRID:grid.1049.c) (ISNI:0000 0001 2294 1395) 
2  University and Hospital Trust of Verona, ARC-Net Centre for Applied Research on Cancer, Verona, Italy (GRID:grid.411475.2) (ISNI:0000 0004 1756 948X) 
3  The Institute of Cancer Research, Division of Molecular Pathology, London, UK (GRID:grid.18886.3f) (ISNI:0000 0001 1271 4623); The Royal Marsden Hospital, London, UK (GRID:grid.424926.f) (ISNI:0000 0004 0417 0461) 
4  University and Hospital Trust of Verona, ARC-Net Centre for Applied Research on Cancer, Verona, Italy (GRID:grid.411475.2) (ISNI:0000 0004 1756 948X); University of Verona, Section of Pathology, Department of Diagnostics and Public Health, Verona, Italy (GRID:grid.5611.3) (ISNI:0000 0004 1763 1124) 
5  University and Hospital Trust of Verona, ENETS Center of Excellence, Verona, Italy (GRID:grid.411475.2) (ISNI:0000 0004 1756 948X); University and Hospital Trust of Verona, Section of Oncology, Department of Medicine, Verona, Italy (GRID:grid.411475.2) (ISNI:0000 0004 1756 948X) 
6  University and Hospital Trust of Verona, ENETS Center of Excellence, Verona, Italy (GRID:grid.411475.2) (ISNI:0000 0004 1756 948X); University and Hospital Trust of Verona, The Pancreas Institute, Verona, Italy (GRID:grid.411475.2) (ISNI:0000 0004 1756 948X) 
7  University of Glasgow, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, Glasgow, UK (GRID:grid.8756.c) (ISNI:0000 0001 2193 314X); University of Glasgow, Glasgow Royal Infirmary, Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, Glasgow, UK (GRID:grid.8756.c); Glasgow Royal Infirmary, West of Scotland Pancreatic Unit, Glasgow, UK (GRID:grid.411714.6) (ISNI:0000 0000 9825 7840) 
8  University of Glasgow, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, Glasgow, UK (GRID:grid.8756.c) (ISNI:0000 0001 2193 314X); University of Heidelberg, Department of General Surgery, Heidelberg, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373) 
9  University of Glasgow, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, Glasgow, UK (GRID:grid.8756.c) (ISNI:0000 0001 2193 314X); Queen Elizabeth University Hospital, Greater Glasgow & Clyde NHS, Department of Pathology, Glasgow, UK (GRID:grid.8756.c) 
10  Baylor College of Medicine, Department of Molecular and Human Genetics, Human Genome Sequencing Center, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X); Baylor College of Medicine, Michael E. DeBakey Department of Surgery and The Elkins Pancreas Center, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X) 
11  Baylor College of Medicine, Department of Molecular and Human Genetics, Human Genome Sequencing Center, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X) 
12  Baylor College of Medicine, Department of Molecular and Human Genetics, Human Genome Sequencing Center, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X); Baylor College of Medicine, Human Genome Sequencing Center, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X) 
13  Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Department of Pathology, Milan, Italy (GRID:grid.417893.0) (ISNI:0000 0001 0807 2568) 
14  University of Glasgow, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, Glasgow, UK (GRID:grid.8756.c) (ISNI:0000 0001 2193 314X); Ospedale Pederzoli, Peschiera del Garda, Verona, Italy (GRID:grid.8756.c) 
15  Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Sydney, Australia (GRID:grid.415306.5) (ISNI:0000 0000 9983 6924) 
16  Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Sydney, Australia (GRID:grid.415306.5) (ISNI:0000 0000 9983 6924); Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Melbourne, Australia (GRID:grid.431578.c) (ISNI:0000 0004 5939 3689) 
17  Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Melbourne, Australia (GRID:grid.431578.c) (ISNI:0000 0004 5939 3689) 
18  Royal North Shore Hospital, St Leonards, Australia (GRID:grid.412703.3) (ISNI:0000 0004 0587 9093) 
19  Bankstown Hospital, Bankstown, Australia (GRID:grid.412703.3) 
20  Liverpool Hospital, Liverpool, Australia (GRID:grid.415994.4) (ISNI:0000 0004 0527 9653) 
21  St Vincent’s Hospital, Darlinghurst, Australia (GRID:grid.437825.f) (ISNI:0000 0000 9119 2677) 
22  Westmead Hospital, Westmead, Australia (GRID:grid.413252.3) (ISNI:0000 0001 0180 6477) 
23  Royal Prince Alfred Hospital, Camperdown, Australia (GRID:grid.413249.9) (ISNI:0000 0004 0385 0051) 
24  Liverpool Hospital, Liverpool, Australia (GRID:grid.415994.4) (ISNI:0000 0004 0527 9653); Royal Prince Alfred Hospital, Camperdown, Australia (GRID:grid.413249.9) (ISNI:0000 0004 0385 0051) 
25  University of Glasgow, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, Glasgow, UK (GRID:grid.8756.c) (ISNI:0000 0001 2193 314X) 
26  Prince of Wales Hospital, Randwick, Australia (GRID:grid.415193.b) 
27  Fremantle Hospital, Fremantle, Australia (GRID:grid.415051.4) (ISNI:0000 0004 0402 6638) 
28  Epworth HealthCare, Richmond, Australia (GRID:grid.414539.e) (ISNI:0000 0001 0459 5396) 
29  Royal Adelaide Hospital, Adelaide, Australia (GRID:grid.416075.1) (ISNI:0000 0004 0367 1221) 
30  Flinders Medical Centre, Bedford Park, Australia (GRID:grid.414925.f) (ISNI:0000 0000 9685 0624) 
31  Envoi Pathology, Herston, Australia (GRID:grid.414925.f) 
32  Princess Alexandra Hospital, Woolloongabba, Australia (GRID:grid.412744.0) (ISNI:0000 0004 0380 2017) 
33  Austin Hospital, Heidelberg, Australia (GRID:grid.414094.c) (ISNI:0000 0001 0162 7225) 
34  Johns Hopkins Medical Institute, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
35  University and Hospital Trust of Verona, ARC-Net Centre for Applied Research on Cancer, Verona, Italy (GRID:grid.411475.2) (ISNI:0000 0004 1756 948X); University and Hospital Trust of Verona, The Pancreas Institute, Verona, Italy (GRID:grid.411475.2) (ISNI:0000 0004 1756 948X) 
36  University of Verona, Section of Pathology, Department of Diagnostics and Public Health, Verona, Italy (GRID:grid.5611.3) (ISNI:0000 0004 1763 1124) 
37  University and Hospital Trust of Verona, The Pancreas Institute, Verona, Italy (GRID:grid.411475.2) (ISNI:0000 0004 1756 948X) 
38  Ospedale Pederzoli, Peschiera del Garda, Verona, Italy (GRID:grid.411475.2) 
39  University of Sydney, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X); Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Sydney, Australia (GRID:grid.415306.5) (ISNI:0000 0000 9983 6924) 
40  QIMR Berghofer Medical Research Institute, Brisbane, Australia (GRID:grid.1049.c) (ISNI:0000 0001 2294 1395); The University of Queensland, Institute for Molecular Bioscience, Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537) 
41  University and Hospital Trust of Verona, ARC-Net Centre for Applied Research on Cancer, Verona, Italy (GRID:grid.411475.2) (ISNI:0000 0004 1756 948X); University of Verona, Section of Pathology, Department of Diagnostics and Public Health, Verona, Italy (GRID:grid.5611.3) (ISNI:0000 0004 1763 1124); University and Hospital Trust of Verona, ENETS Center of Excellence, Verona, Italy (GRID:grid.411475.2) (ISNI:0000 0004 1756 948X) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
23993642
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s42003-020-01469-0
ProQuest document ID
2485937386
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.