Molecular Characterisation of Non-functional Pancreatic Neuroendocrine Tumours

Robust molecular stratification provides insights into cell lineage correlates

On 1 July 2019, a research team composed from the investigators from US, Spain and the Netherlands published in the Nature Medicine a robust molecular stratification that provides insights into cell lineage correlates of non-functional pancreatic neuroendocrine tumours (pNETs), accurately predicts disease course and can inform postoperative clinical decisions.

The authors wrote in the study background that most pNETs do not produce excess hormones. Therefore, such tumours are considered non-functional. However, clinical behaviours vary widely and distant metastases are eventually lethal, so benefit from biological classifications might be in guiding the treatment.

By using enhancer maps to infer gene regulatory programmes, the research team found that non-functional pNETs fall into two major subtypes, with epigenomes and transcriptomes that partially resemble islet α- and β-cells.

In particular, transcription factors ARX and PDX1 specify these normal cells. In total, 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-positive/PDX1-negative tumours 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.

The study team was composed from the researchers from Dana-Farber Cancer Institute, Boston, MA, US; Hospital La Paz Institute for Health Research, Madrid, Spain; Broad Institute of Harvard and MIT, Cambridge, MA, US; Massachusetts General Hospital and Harvard Medical School, Boston, MA, US; UMC Utrecht Cancer Center, Utrecht, the Netherlands; Amsterdam UMC, Amsterdam, the Netherlands; Johns Hopkins University School of Medicine, Baltimore, MD, US; and Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, US. Paloma Cejas and Yotam Drier contributed equally. They are both based in the Lautenberg Center for Immunology and Cancer Research, Hebrew University, Faculty of Medicine, Jerusalem, Israel.

The study has been supported by the Neuroendocrine Tumor Research Foundation, the SPORE program of the US National Cancer Institute in gastrointestinal cancers, the North American Neuroendocrine Tumor Society and a grant from Instituto de Salud Carlos III of the Spanish Economy and Competitiveness Ministry.

A group of authors contributed to the Dutch MEN1 Study Group database and tissue repository.

ChIP-seq and RNA-seq data have been deposited in the National Center Biotechnology Information’s GEO under GSE116356.


Cejas P, Drier Y, Dreijerink KMA, et al. Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors. Nature Medicine; Published online 1 July 2019. doi: 10.1038/s41591-019-0493-4.