DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association
Vanessa Lakis, Rita T. Lawlor, Felicity Newell, Ann‐Marie Patch, Andrea Mafficini, Anguraj Sadanandam, Lambros T. Koufariotis, Rebecca L. Johnston, Conrad Leonard, Scott Wood, Borislav C. Rusev, Vincenzo Corbo, Claudio Luchini, Sara Cingarlini, Luca Landoni, Roberto Salvia, Michèle Milella, David K. Chang, Peter J. Bailey, Nigel B. Jamieson, Fraser R. Duthie, Marie‐Claude Gingras, Donna M. Muzny, David A. Wheeler, Richard A. Gibbs, Massimo Milione, APGI, Lorraine A. Chantrill, Paul Timpson, Angela Chou, Marina Pajic, Angela Murphy, Tanya Dwarte, David Hermann, Claire Vennin, Thomas R. Cox, Brooke Pereira, Shona Ritchie, Daniel A. Reed, Cecilia R. Chambers, Xanthe L. Metcalf, Max Nobis, Pamela Mukhopadhyay, Venkateswar Addala, Stephen H. Kazakoff, Oliver Holmes, Qinying Xu, Oliver Hofmann, Jaswinder S. Samra, Nick Pavlakis, Jennifer Arena, Hilda A. High, Ray Asghari, Neil D. Merrett, Darren Pavey, Amitabha Das, Peter H. Cosman, Kasim Ismail, Chelsie O’Connnor, Alina Stoita, David Williams, Allan Spigellman, Vincent Lam, Duncan McLeod, Judy Kirk, James G. Kench, Peter Grimison, Charbel Sandroussi, Annabel Goodwin, R. Scott Mead, Katherine Tucker, Lesley Andrews, Michael Texler, Cindy Forest, Mo Ballal, David Fletcher, Epworth Health Care, Nikolajs Zeps, Nan Q. Nguyen, Andrew Ruszkiewicz, Chris Worthley, John Chen, Mark E. Brooke‐Smith, Virginia Papangelis, Envoi Pathology, Andrew D. Clouston, Andrew P. Barbour, Thomas J. O’Rourke, Jonathan W. Fawcett, Kellee Slater, Michael Hatzifotis, Peter Hodgkinson, Mehrdad Nikfarjam, James R. Eshleman, Ralph H. Hruban, Christopher L. Wolfgang, Judith Dixon, ARC-Net, Maria Scardoni, Claudio Bassi
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.