Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors
| Autor: | Menno R. Vriens, Carlos Fernandez-del Castillo, Henry W. Long, Alba Font-Tello, Folkert H.M. Morsink, Mindy K. Graham, Paloma Cejas, Elfi B. Conemans, Koen M.A. Dreijerink, Vikram Deshpande, Holly Whitton, Christopher M. Heaphy, Michaela Bowden, Bradley E. Bernstein, Elizabeth Gaskell, Gerlof D. Valk, Yotam Drier, Lodewijk A.A. Brosens, Noam Shoresh, Annacarolina da Silva, Ewa Sicinska, Daniel C. Chung, Tomer Adar, Matthew H. Kulke, Cristina R. Ferrone, Charles B. Epstein, Ramesh A. Shivdasani |
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| Přispěvatelé: | Academic Medical Center, Amsterdam Gastroenterology Endocrinology Metabolism |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Biology Neuroendocrine tumors medicine.disease_cause Bioinformatics General Biochemistry Genetics and Molecular Biology Article PNET prognosis Transcriptome 03 medical and health sciences 0302 clinical medicine Proto-Oncogene Proteins medicine Humans Cell Lineage Enhancer Transcription factor Gene Homeodomain Proteins Mutation cancer sub-classification General Medicine Telomere medicine.disease 3. Good health Pancreatic Neoplasms Enhancer Elements Genetic 030104 developmental biology 030220 oncology & carcinogenesis Trans-Activators PDX1 cancer enhancer landscapes pancreatic endocrine ontogeny neuroendocrine tumors Transcription Factors |
| Zdroj: | Nature medicine, 25(8), 1264-1269. Nature Publishing Group Nature medicine Nature Medicine, 25(8), 1264-1269. Nature Publishing Group |
| ISSN: | 1078-8956 |
| DOI: | 10.1038/s41591-019-0493-4 |
| Popis: | 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 sub-types whose epigenomes and transcriptomes partially resemble islet alpha and beta 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 sub-type, in cases with alternative lengthening of telomeres (ALT). 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 post-operative clinical decisions. |
| Databáze: | OpenAIRE |
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