DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors

Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
Science (Impact Factor: 33.61). 03/2011; 331(6021):1199-203. DOI: 10.1126/science.1200609
Source: PubMed


Pancreatic neuroendocrine tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. To explore the
genetic basis of PanNETs, we determined the exomic sequences of 10 nonfamilial PanNETs and then screened the most commonly
mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling:
44% of the tumors had somatic inactivating mutations in MEN1, which encodes menin, a component of a histone methyltransferase complex, and 43% had mutations in genes encoding either
of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain–associated protein) and
ATRX (α thalassemia/mental retardation syndrome X-linked). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. We also found mutations in genes in the mTOR (mammalian target of rapamycin)
pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors.

Download full-text


Available from: Roeland Frederik de Wilde,
  • Source
    • "DISCUSSION A growing body of evidence obtained in both mouse and human cells indicates that ATRX is essential for maintenance of chromosome stability during mitosis and meiosis (De La Fuente et al., 2004; Ritchie et al., 2008; Baumann et al., 2010). A high frequency of human pancreatic neuroendocrine tumors and pediatric glioblastomas exhibit loss of ATRX function (Elsasser et al., 2011; Jiao et al., 2011; Molenaar et al., 2012) and mutations in the human ATRX gene have been recently detected in aggressive high-stage neuroblastomas that exhibit complex chromosomal rearrangements and chromothripsis, an extreme form of chromosome shattering (Jones and Jallepalli, 2012; Molenaar et al., 2012 "
    [Show abstract] [Hide abstract]
    ABSTRACT: A striking proportion of human cleavage-stage embryos exhibit chromosome instability (CIN). Notably, until now, no experimental model has been described to determine the origin and mechanisms of complex chromosomal rearrangements. Here, we examined mouse embryos deficient for the chromatin remodeling protein ATRX to determine the cellular mechanisms activated in response to CIN. We demonstrate that ATRX is required for silencing of major satellite transcripts in the maternal genome, where it confers epigenetic asymmetry to pericentric heterochromatin during the transition to the first mitosis. This stage is also characterized by a striking kinetochore size asymmetry established by differences in CENP-C protein between the parental genomes. Loss of ATRX results in increased centromeric mitotic recombination, a high frequency of sister chromatid exchanges and double strand DNA breaks, indicating the formation of mitotic recombination break points. ATRX-deficient embryos exhibit a twofold increase in transcripts for aurora kinase B, the centromeric cohesin ESCO2, DNMT1, the ubiquitin-ligase (DZIP3) and the histone methyl transferase (EHMT1). Thus, loss of ATRX activates a pathway that integrates epigenetic modifications and DNA repair in response to chromosome breaks. These results reveal the cellular response of the cleavage-stage embryo to CIN and uncover a mechanism by which centromeric fission induces the formation of large-scale chromosomal rearrangements. Our results have important implications to determine the epigenetic origins of CIN that lead to congenital birth defects and early pregnancy loss, as well as the mechanisms involved in the oocyte to embryo transition.
    Development 05/2015; 142(10). DOI:10.1242/dev.118927 · 6.46 Impact Factor
  • Source
    • "Both ATRX and Daxx are required for the deposition of H3.3 at these repeats, and mutations in the ATRX/Daxx/H3.3 pathway have been linked to certain cancers and an alternative lengthening of telomeres (ALT) phenotype (Heaphy et al., 2011; Jiao et al., 2011; Lovejoy et al., 2012; Schwartzentruber et al., 2012), demonstrating the importance of this pathway in maintaining chromatin integrity and, with it, genomic stability. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Histone H3.3 is a replication-independent histone variant, which replaces histones that are turned over throughout the entire cell cycle. H3.3 deposition at euchromatin is dependent on HIRA, whereas ATRX/Daxx deposits H3.3 at pericentric heterochromatin and telomeres. The role of H3.3 at heterochromatic regions is unknown, but mutations in the ATRX/Daxx/H3.3 pathway are linked to aberrant telomere lengthening in certain cancers. In this study, we show that ATRX-dependent deposition of H3.3 is not limited to pericentric heterochromatin and telomeres but also occurs at heterochromatic sites throughout the genome. Notably, ATRX/H3.3 specifically localizes to silenced imprinted alleles in mouse ESCs. ATRX KO cells failed to deposit H3.3 at these sites, leading to loss of the H3K9me3 heterochromatin modification, loss of repression, and aberrant allelic expression. We propose a model whereby ATRX-dependent deposition of H3.3 into heterochromatin is normally required to maintain the memory of silencing at imprinted loci. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 11(3). DOI:10.1016/j.celrep.2015.03.036 · 8.36 Impact Factor
    • "The role of mTOR inhibitors has been widely studied in low-grade or advanced pancreatic neuroendocrine tumors, and mTOR inhibitors have shown positive activity; however, these studies did not specify whether the patients had VHL or sporadic disease (Riccardi et al., 2012). Role of mTOR inhibitors is further supported by identification of mutation in the genes in the mTOR pathway in 14% of patients with sporadic PNET (Jiao et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Von Hippel-Lindau disease, Cowden syndrome, and Proteus syndrome are cancer syndromes which affect multiple organs and lead to significant decline in quality of life in affected patients. These syndromes are rare and typically affect the adolescent and young adult population, resulting in greater cumulative years of life lost. Improved understanding of the underpinnings of the genetic pathways underlying these syndromes and the rapid evolution of targeted therapies in general have made it possible to develop therapeutic options for these patients and other genetic cancer syndromes. Targeted therapies especially antiangiogenics and inhibitors of the PIK3CA/AKT/mTOR signaling pathway have shown activity in selected group of patients affected by these syndromes or in patients harboring specific sporadic mutations which are otherwise characteristic of these syndromes. Unfortunately due to the rare nature, patients with these syndromes are not the focus of clinical trials and unique results seen in these patients can easily go unnoticed. Most of the data suggesting benefits of targeted therapies are either case reports or small case series. Thus, a literature review was indicated. In this review we explore the use of molecularly targeted therapy options in Von Hippel-Lindau disease, Cowden syndrome, and Proteus syndrome.
    Discovery medicine 02/2015; 19(103):109-116. · 3.63 Impact Factor
Show more