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Nat Med DOI:10.1038/s41591-019-0493-4

Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors.

Publication TypeJournal Article
Year of Publication2019
AuthorsCejas, P, Drier, Y, Dreijerink, KMA, Brosens, LAA, Deshpande, V, Epstein, CB, Conemans, EB, Morsink, FHM, Graham, MK, Valk, GD, Vriens, MR, Del Castillo, CFernandez-, Ferrone, CR, Adar, T, Bowden, M, Whitton, HJ, da Silva, A, Font-Tello, A, Long, HW, Gaskell, E, Shoresh, N, Heaphy, CM, Sicinska, E, Kulke, MH, Chung, DC, Bernstein, BE, Shivdasani, RA
JournalNat Med
Date Published2019 08
KeywordsCell Lineage, Enhancer Elements, Genetic, Homeodomain Proteins, Humans, Mutation, Pancreatic Neoplasms, Proto-Oncogene Proteins, Telomere, Trans-Activators, Transcription Factors

Most 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 subtypes, with epigenomes and transcriptomes that partially resemble islet α- and β-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 ARXPDX1 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.


Alternate JournalNat Med
PubMed ID31263286
PubMed Central IDPMC6919319
Grant ListP50 CA127003 / CA / NCI NIH HHS / United States