DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association
Vanessa Lakis(QIMR Berghofer Medical Research Institute), Rita T. Lawlor(University of Verona), Felicity Newell(QIMR Berghofer Medical Research Institute), Ann‐Marie Patch(QIMR Berghofer Medical Research Institute), Andrea Mafficini(University of Verona), Anguraj Sadanandam(Institute of Cancer Research), Lambros T. Koufariotis(QIMR Berghofer Medical Research Institute), Rebecca L. Johnston(QIMR Berghofer Medical Research Institute), Conrad Leonard(QIMR Berghofer Medical Research Institute), Scott Wood(QIMR Berghofer Medical Research Institute), Borislav C. Rusev(University of Verona), Vincenzo Corbo(University of Verona), Claudio Luchini(University of Verona), Sara Cingarlini(University of Verona), Luca Landoni, Roberto Salvia, Michèle Milella(University of Verona), David K. Chang(Glasgow Royal Infirmary), Peter J. Bailey(Heidelberg University), Nigel B. Jamieson(Glasgow Royal Infirmary), Fraser R. Duthie(Queen Elizabeth University Hospital), Marie‐Claude Gingras(Baylor College of Medicine), Donna M. Muzny(Baylor College of Medicine), David A. Wheeler(Baylor College of Medicine), Richard A. Gibbs(Baylor College of Medicine), Massimo Milione(Fondazione IRCCS Istituto Nazionale dei Tumori), APGI(University of Glasgow), Lorraine A. Chantrill(Garvan Institute of Medical Research), Paul Timpson(Garvan Institute of Medical Research), Angela Chou(Garvan Institute of Medical Research), Marina Pajic(Garvan Institute of Medical Research), Angela Murphy(Garvan Institute of Medical Research), Tanya Dwarte(Garvan Institute of Medical Research), David Hermann(Garvan Institute of Medical Research), Claire Vennin(Garvan Institute of Medical Research), Thomas R. Cox(Garvan Institute of Medical Research), Brooke Pereira(Garvan Institute of Medical Research), Shona Ritchie(Garvan Institute of Medical Research), Daniel A. Reed(Garvan Institute of Medical Research), Cecilia R. Chambers(Garvan Institute of Medical Research), Xanthe L. Metcalf(Garvan Institute of Medical Research), Max Nobis(Garvan Institute of Medical Research), Pamela Mukhopadhyay(QIMR Berghofer Medical Research Institute), Venkateswar Addala(QIMR Berghofer Medical Research Institute), Stephen H. Kazakoff(QIMR Berghofer Medical Research Institute), Oliver Holmes(QIMR Berghofer Medical Research Institute), Qinying Xu(The University of Melbourne), Oliver Hofmann(The University of Sydney), Jaswinder S. Samra(The University of Sydney), Nick Pavlakis(Royal North Shore Hospital), Jennifer Arena(Royal North Shore Hospital), Hilda A. High(Royal North Shore Hospital), Ray Asghari(Bankstown Lidcombe Hospital), Neil D. Merrett(Bankstown Lidcombe Hospital), Darren Pavey(Bankstown Lidcombe Hospital), Amitabha Das(Bankstown Lidcombe Hospital), Peter H. Cosman(Liverpool Hospital), Kasim Ismail(Liverpool Hospital), Chelsie O’Connnor(St Vincent's Hospital Sydney), Alina Stoita(St Vincent's Hospital Sydney), David Williams(St Vincent's Hospital Sydney), Allan Spigellman(Westmead Hospital), Vincent Lam(Westmead Hospital), Duncan McLeod(Westmead Hospital), Judy Kirk(Royal Prince Alfred Hospital), James G. Kench(Royal Prince Alfred Hospital), Peter Grimison(Royal Prince Alfred Hospital), Charbel Sandroussi(Royal Prince Alfred Hospital), Annabel Goodwin(Royal Prince Alfred Hospital), R. Scott Mead(Prince of Wales Hospital), Katherine Tucker(Prince of Wales Hospital), Lesley Andrews(Fremantle Hospital), Michael Texler(Fremantle Hospital), Cindy Forest(Fremantle Hospital), Mo Ballal(Fremantle Hospital), David Fletcher(Epworth Hospital), Epworth Health Care(Royal Adelaide Hospital), Nikolajs Zeps(Royal Adelaide Hospital), Nan Q. Nguyen(Royal Adelaide Hospital), Andrew Ruszkiewicz(Royal Adelaide Hospital), Chris Worthley(Royal Adelaide Hospital), John Chen(Flinders Medical Centre), Mark E. Brooke‐Smith(Flinders Medical Centre), Virginia Papangelis(Princess Alexandra Hospital), Envoi Pathology(Princess Alexandra Hospital), Andrew D. Clouston(Princess Alexandra Hospital), Andrew P. Barbour(Princess Alexandra Hospital), Thomas J. O’Rourke(Princess Alexandra Hospital), Jonathan W. Fawcett(Princess Alexandra Hospital), Kellee Slater(Austin Hospital), Michael Hatzifotis(Johns Hopkins University), Peter Hodgkinson(Johns Hopkins University), Mehrdad Nikfarjam(Johns Hopkins University), James R. Eshleman(Johns Hopkins University), Ralph H. Hruban(University of Verona), Christopher L. Wolfgang(Johns Hopkins University), Judith Dixon(University of Verona), ARC-Net(University of Verona), Maria Scardoni(University of Verona), Claudio Bassi(University of Verona), Sonia Grimaldi(University of Verona), Cinzia Cantù(University of Verona), Giada Bonizzato(University of Verona), Samantha Bersani(University of Verona), Davide Antonello(University of Verona), Liliana Piredda(University of Verona), Nicola Sperandio(University of Verona), Stefano Barbi(University of Verona), Paola Merlini(University of Verona), Paolo Pederzoli(QIMR Berghofer Medical Research Institute), Jaswinder S. Samra(The University of Sydney), Anthony J. Gill(The University of Sydney), Amber L. Johns(Garvan Institute of Medical Research), John V. Pearson(QIMR Berghofer Medical Research Institute), Andrew V. Biankin(University of Glasgow), Sean M. Grimmond(The University of Melbourne), Nicola Waddell(The University of Queensland), Kátia Nones(QIMR Berghofer Medical Research Institute), Aldo Scarpa(University of Verona)
Cited by 51Open Access
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.
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