Format

Send to

Choose Destination
Nat Med. 2019 Aug;25(8):1260-1265. doi: 10.1038/s41591-019-0493-4. Epub 2019 Jul 1.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
2
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
3
Translational Oncology Laboratory, Hospital La Paz Institute for Health Research, Madrid, Spain.
4
Broad Institute of Harvard and MIT, Cambridge, MA, USA. yotam.drier@mail.huji.ac.il.
5
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. yotam.drier@mail.huji.ac.il.
6
Lautenberg Center for Immunology and Cancer Research, Hebrew University, Faculty of Medicine, Jerusalem, Israel. yotam.drier@mail.huji.ac.il.
7
Department of Endocrine Oncology, UMC Utrecht Cancer Center, Utrecht, the Netherlands.
8
Department of Internal Medicine, Amsterdam UMC, Amsterdam, the Netherlands.
9
Department of Pathology, UMC Utrecht Cancer Center, Utrecht, the Netherlands.
10
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
11
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
12
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
13
Department of Surgical Oncology, UMC Utrecht Cancer Center, Utrecht, the Netherlands.
14
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
15
Department of Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
16
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
17
Departments of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
18
Broad Institute of Harvard and MIT, Cambridge, MA, USA. bernstein.bradley@mgh.harvard.edu.
19
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. bernstein.bradley@mgh.harvard.edu.
20
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. ramesh_shivdasani@dfci.harvard.edu.
21
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. ramesh_shivdasani@dfci.harvard.edu.
22
Departments of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. ramesh_shivdasani@dfci.harvard.edu.

Abstract

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.

PMID:
31263286
DOI:
10.1038/s41591-019-0493-4
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center