Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
Nat Med. 2019 Aug;25(8):1260-1265. doi: 10.1038/s41591-019-0493-4. Epub 2019 Jul 1.
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.
大多数胰腺神经内分泌肿瘤（PNET）不会产生过多的激素，因此被认为是“无功能的”。由于临床行为差异很大，远处转移最终是致命的，因此生物分类可能有助于指导治疗。我们利用增强子图谱来推断基因调控程序，发现无功能 PNET 分为两个主要亚型，其表观基因组和转录组部分类似于胰岛的 α 和 β 细胞。转录因子 ARX 和 PDX1 分别指定这些正常细胞，在 142 个无功能 PNET 中，有 84%表达了一个或另一个因子，偶尔两者都表达。在 103 例病例中，远处复发几乎仅发生在 ARXPDX1 肿瘤患者中，并且在该亚型中，发生在端粒延长替代的病例中。这些截然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，无论 MEN1 突变如何，都有这种情况发生。这种强大的分子分层为无功能 PNET 的细胞谱系相关性提供了深入的了解，能够准确预测疾病进程，并为术后临床决策提供信息。
