Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered ‘non-functional’1–3. As clinical behaviors vary widely and distant metastases are eventually lethal2,4, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major subtypes, with epigenomes and transcriptomes that partially resemble islet α- and β-cells. Transcription factors ARX and PDX1 specify these normal cells, respectively5,6, and 84% of 142 non-functional PNETs expressed one or the other factor, occasionally both. Among 103 cases, distant relapses occurred almost exclusively in patients with ARX+PDX1− tumors and, within this subtype, in cases with alternative lengthening of telomeres. These markedly different outcomes belied similar clinical presentations and histology and, in one cohort, occurred irrespective of MEN1 mutation. This robust molecular stratification provides insight into cell lineage correlates of non-functional PNETs, accurately predicts disease course and can inform postoperative clinical decisions.
Bibliographical noteFunding Information:
The present study has been supported by the Neuroendocrine Tumor Research Foundation (R.A.S., B.E.B., M.H.K. and D.C.C.), the SPORE program in gastrointestinal cancers (P50CA127003—National Cancer Institute, R.A.S.), the North American Neuroendocrine Tumor Society (C.M.H.) and a grant (no. PI18-01604 to P.C.) from Instituto de Salud Carlos III of the Spanish Economy and Competitiveness Ministry.
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.