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ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup

Chang S Chan, Saurabh V Laddha, Peter Lewis, Matthew Koletsky, Kenneth Robzyk, Edaise Da Silva, Paula J. Torres, Brian Untch, Promita Bose, Timothy A. Chan, David S. Klimstra, C. David Allis, Laura H. Tang
doi: https://doi.org/10.1101/195214
Chang S Chan
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USARutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
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Saurabh V Laddha
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
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Peter Lewis
Epigenetics Theme, Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI
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Matthew Koletsky
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA
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Kenneth Robzyk
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
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Edaise Da Silva
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
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Paula J. Torres
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
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Brian Untch
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
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Promita Bose
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY10065, USA
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Timothy A. Chan
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY10065, USA
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David S. Klimstra
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
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C. David Allis
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA
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Laura H. Tang
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
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Abstract

The most commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. Little is known about the cells-of-origin for non-functional neuroendocrine tumors. Here, we genotyped 64 PanNETs for mutations in ATRX, DAXX, and MEN1 and found 37 tumors (58%) carry mutations in these three genes (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis on 33 randomly selected cases to reveal two distinct subgroups with one group consisting entirely of A-D-M mutant PanNETs. Two biomarkers differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX gene expression and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha cells (pval < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells.

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Posted September 28, 2017.
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ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup
Chang S Chan, Saurabh V Laddha, Peter Lewis, Matthew Koletsky, Kenneth Robzyk, Edaise Da Silva, Paula J. Torres, Brian Untch, Promita Bose, Timothy A. Chan, David S. Klimstra, C. David Allis, Laura H. Tang
bioRxiv 195214; doi: https://doi.org/10.1101/195214
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ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup
Chang S Chan, Saurabh V Laddha, Peter Lewis, Matthew Koletsky, Kenneth Robzyk, Edaise Da Silva, Paula J. Torres, Brian Untch, Promita Bose, Timothy A. Chan, David S. Klimstra, C. David Allis, Laura H. Tang
bioRxiv 195214; doi: https://doi.org/10.1101/195214

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