Cejas, PalomaDrier, YotamBrosens, Lodewijk A. A.Deshpande, VikramMorsink, Folkert H. M.Graham, Mindy K.Valk, Gerlof D.Vriens, Menno R.Fernandez-Del Castillo, CarlosFabiana Lucia da Silva, AnnacarolinaFont-Tello, AlbaHeaphy, Christopher M.Sicinska, EwaDreijerink, KoenEpstein, CharlesConemans, ElfiFerrone, CristinaAdar, TomerBowden, MichaelaWhitton, HollyLong, HenryGaskell, ElizabethShoresh, NoamKulke, MatthewChung, DanielBernstein, BradleyShivdasani, Ramesh2022-08-252019-07-01Cejas, Paloma, Yotam Drier, Koen M.A. Dreijerink, Lodewijk A.A. Brosens, Vikram Deshpande, Charles B. Epstein, Elfi B. Conemans, Folkert H.M. Morsink, et al. 2019. Enhancer Signatures Stratify and Predict Outcomes of Non-functional Pancreatic Neuroendocrine Tumors. Nature Medicine 25, no. 8: 1260-265.1078-89561546-170Xhttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37373045Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered ‘non-functional’. As clinical behaviors vary widely and distant metastases are eventually lethal, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major sub-types whose epigenomes and transcriptomes partially resemble islet alpha and beta cells. Transcription factors ARX and PDX1 specify these normal cells, respectively, 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 sub-type, in cases with alternative lengthening of telomeres (ALT). 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 post-operative clinical decisions.en-USGeneral Biochemistry, Genetics and Molecular BiologyGeneral MedicineJournal Article2022-08-2510.1038/s41591-019-0493-4