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: 31.48). 03/2011; 331(6021):1199-203. DOI: 10.1126/science.1200609
Source: PubMed

ABSTRACT 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.

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Available from: Roeland Frederik de Wilde, Aug 30, 2015
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    • "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 "
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    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 · 6.27 Impact Factor
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    • "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. "
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    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
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    • "In addition to epigenetic mechanisms, Jiao et al. [12] recently identified gene alterations in alpha thalassemia/ mental retardation syndrome X-linked (ATRX)/death domainassociated protein (DAXX) and mammalian target of rapamycin (mTOR) genes in panNETs. Physiologically, these proteins regulate apoptosis, cell growth, and chromatin remodeling. "
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