Nature medicine · 2019
Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Cejas Paloma, Drier Yotam, Dreijerink Koen M A, Brosens Lodewijk A A, Deshpande Vikram, Epstein Charles B, Conemans Elfi B, Morsink Folkert H M, Graham Mindy K, Valk Gerlof D, Vriens Menno R, Castillo Carlos Fernandez-Del, Ferrone Cristina R, Adar Tomer, Bowden Michaela, Whitton Holly J, Da Silva Annacarolina, Font-Tello Alba, Long Henry W, Gaskell Elizabeth, Shoresh Noam, Heaphy Christopher M, Sicinska Ewa, Kulke Matthew H, Chung Daniel C, Bernstein Bradley E, Shivdasani Ramesh A
Аннотация
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.