DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association
Authors: Lakis Vanessa , Lawlor Rita T. , Newell Felicity , Patch Ann-Marie , Mafficini Andrea , Sadanandam Anguraj , Koufariotis Lambros T. , Johnston Rebecca L. , Leonard Conrad , Wood Scott , Rusev Borislav , Corbo Vincenzo , Luchini Claudio , Cingarlini Sara , Landoni Luca , Salvia Roberto , Milella Michele , Chang David , Bailey Peter , Jamieson Nigel B. , Duthie Fraser , Gingras Marie-Claude , Muzny Donna M. , Wheeler David A. , Gibbs Richard A. , Milione Massimo ,   APGI,   Garvan Institute of Medical Research, Chantrill Lorraine A. , Timpson Paul , Chou Angela , Pajic Marina , Murphy Angela , Dwarte Tanya , Hermann David , Vennin Claire , Cox Thomas R. , Pereira Brooke , Ritchie Shona , Reed Daniel A. , Chambers Cecilia R. , Metcalf Xanthe , Nobis Max ,   QIMR Berghofer Medical Research Institute, Mukhopadhyay Pamela , Addala Venkateswar , Kazakoff Stephen , Holmes Oliver , Xu Qinying ,   University of Melbourne: Centre for Cancer Research, Hofmann Oliver ,   Royal North Shore Hospital, Samra Jaswinder S. , Pavlakis Nick , Arena Jennifer , High Hilda A. ,   Bankstown Hospital, Asghari Ray , Merrett Neil D. , Pavey Darren , Das Amitabha ,   Liverpool Hospital, Cosman Peter H. , Ismail Kasim , O’Connnor Chelsie ,   St Vincent’s Hospital, Stoita Alina , Williams David , Spigellman Allan ,   Westmead Hospital, Lam Vincent W. , McLeod Duncan , Kirk Judy ,   Royal Prince Alfred Hospital Chris O’Brien Lifehouse, Kench James G. , Grimison Peter , Sandroussi Charbel , Goodwin Annabel ,   Prince of Wales Hospital, Mead R. Scott , Tucker Katherine , Andrews Lesley ,   Fiona Stanley Hospital, Texler Michael , Forest Cindy , Ballal Mo , Fletcher David R. ,   Epworth Health Care, Zeps Nikolajs ,   Royal Adelaide Hospital, Nguyen Nan Q. , Ruszkiewicz Andrew R. , Worthley Chris ,   Flinders Medical Centre, Chen John , Brooke-Smith Mark E. , Papangelis Virginia ,   Envoi Pathology, Clouston Andrew D. ,   Princess Alexandra Hospital, Barbour Andrew P. , O’Rourke Thomas J. , Fawcett Jonathan W. , Slater Kellee , Hatzifotis Michael , Hodgkinson Peter ,   Austin Hospital, Nikfarjam Mehrdad ,   Johns Hopkins Medical Institutes, Eshleman James R. , Hruban Ralph H. , Wolfgang Christopher L. ,   University of Glasgow, Dixon Judith ,   ARC-Net, Scardoni Maria , Bassi Claudio , Grimaldi Sonia , Cantù Cinzia , Bonizzato Giada , Bersani Samantha , Antonello Davide , Piredda Liliana , Sperandio Nicola , Barbi Stefano , Merlini Paola , Pederzoli Paolo , Samra Jaswinder S. , Gill Anthony J. , Johns Amber L. , Pearson John V. , Biankin Andrew V. , Grimmond Sean M. , Waddell Nicola , Nones Katia , Scarpa Aldo 
Published: February 2021

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.