Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors
Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors
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DOI：
10.1038/s41591-019-0493-4
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发表时间：
2019-08-01
期刊：
影响因子：
82.9
通讯作者：
Shivdasani, Ramesh A.
中科院分区：
文献类型：
--
作者：
Cejas, Paloma;Drier, Yotam;Shivdasani, Ramesh A.
大多数胰腺神经内分泌肿瘤（PNTs）不会产生过量的激素，因此被认为是“无功能”（1-3）。由于临床表现差异很大，远处转移最终是致命的（2，4），生物学分类可能会指导治疗。使用增强子图来推断基因调控程序，我们发现，非功能性PNTs分为两个主要亚型，表观基因组和转录组，部分类似于胰岛α和β细胞。转录因子ARX和PDX 1分别指定这些正常细胞（5，6），并且142个非功能性PNTR中的84%表达一种或另一种因子，偶尔两种都表达。在103例病例中，远端复发几乎只发生在ARX（+）PDX 1（-）肿瘤患者中，在该亚型中，发生在端粒交替延长的病例中。这些显著不同的结果掩盖了相似的临床表现和组织学，在一个队列中，发生与MEN 1突变无关。这种强大的分子分层提供了对非功能性PNIPs的细胞谱系相关性的深入了解，准确预测疾病进程，并可以为术后临床决策提供信息。
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 lethal(2,4), 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 alpha- and beta-cells. Transcription factors ARX and PDX1 specify these normal cells, respectively(5,6), 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.