Project title: Transcriptome and methylome of pancreatic NETs with and without ATRX/DAXX mutations

General Description

Nickolas Papadopoulos, PhD, and his team published the results published the results of the first large-scale genome sequencing study of pancreatic neuroendocrine tumors in Science as part of a two-year NETRF grant. Given the importance of the finding, the grant was extended for another two years to explore further the role of DAXX and ATRX mutations in neuroendocrine tumors. 

Dr. Papadopoulos announced the discovery of mutations in two genes (DAXX and ATRX) not previously associated with cancer. Further study of these genes suggests they may play a broader role in the development of not only neuroendocrine cancers but certain types of adult and pediatric brain tumors as well. Identification of mutations within these genes suggests a novel approach to neuroendocrine cancer diagnostics and treatment by targeting epigenetic processes.

DAXX and ATRX are epigenetic regulators, meaning they determine which genes are turned on or off under specific conditions in a cell. While genes contain the instructions for assembling proteins, it is through epigenetic regulation that cells are able to control whether those proteins are actually produced. Mutations within these epigenetic regulating genes can cause them to malfunction, leading to the inactivation of a cancer-suppressing gene, or activation of a cancer-driving gene.

Research Objectives

1. To determine the epigenetic landscape of pancreatic neuroendocrine tumors by studying the gene expression and methylation patterns of pancreatic neuroendocrine tumors with or without DAXX or ATRX mutations.
2. To develop novel therapeutic approaches for patients with neuroendocrine tumors.
3. To study the role of epigenetic regulation in neuroendocrine cancer development.

Abstract

Virtually all the biologic properties of cancer cells are governed by the genetic changes present in them. With the help of CFCF, we have defined the genomic landscapes of pancreatic neuroendocrine tumors. The most intriguing and novel components of these landscapes were mutations of genes called DAXX and ATRX. These genes are master regulators of chromatin packaging – proteins that surround DNA in the nucleus of the cell and determine which genes are turned on or off under specific conditions. In the next phase of our work, we will explore which genes are actually turned on or off in pancreatic neuroendocrine tumors containing mutations of either of these two genes. The long-term objective is to use this information to develop new therapeutic approaches based on a better understanding of these commonly altered pathways in pancreatic neuroendocrine tumors.

Research Publications

Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL, Choti MA, Velculescu VE, Diaz LA Jr, Vogelstein B, Kinzler KW, Hruban RH, Papadopoulos N. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011 Mar 4;331(6021):1199-203. doi: 10.1126/science.1200609. Epub 2011 Jan 20.