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 Rusev, Vincenzo Corbo, Claudio Luchini, Sara Cingarlini, Luca Landoni, Roberto Salvia, Michele Milella, David Chang, Peter Bailey, Nigel B. JamiesonFraser Duthie, Marie Claude Gingras, Donna M. Muzny, David A. Wheeler, Richard A. Gibbs, Massimo Milione, Australian Pancreatic Genome Initiative (APGI), ARC-Net, Paolo Pederzoli, Jaswinder S. Samra, Anthony J. Gill, Amber L. Johns, John V. Pearson, Andrew V. Biankin, Sean M. Grimmond, Nicola Waddell, Katia Nones*, Aldo Scarpa

*Corresponding author for this work

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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.

Original languageEnglish
Article number155
Pages (from-to)1-11
Number of pages11
Journal Communications Biology
Volume4
Issue number1
DOIs
Publication statusPublished - 3 Feb 2021
Externally publishedYes

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Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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