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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.

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association