Altered Telomeres in Tumors with
            <i>ATRX</i>
            and
            <i>DAXX</i>
            Mutations

Heaphy, Christopher M.; Wilde, Roeland F. de; Jiao, Yuchen; Klein, Alison P.; Edil, Barish H.; Shi, Chanjuan; Bettegowda, Chetan; Rodríguez, Fausto J.; Eberhart, Charles G.; Hebbar, Sachin; Offerhaus, G. Johan A.; McLendon, Roger E.; Rasheed, B. Ahmed; He, Yiping; Yan, Hai; Bigner, Darell D.; Oba-Shinjo, Sueli Mieko; Marie, Suely Kazue Nagahashi; Riggins, Gregory J.; Kinzler, Kenneth W.; Vogelstein, Bert; Hruban, Ralph H.; Maitra, Anirban; Papadopoulos, Nickolas; Meeker, Alan K.

doi:10.1126/science.1207313

Cited by 922 publications

(905 citation statements)

References 21 publications

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“…We used antibodies recognizing the C-terminal of ATRX and DAXX proteins, which have been previously shown to be highly correlated with alternative lengthening of telomeres in pancreatic neuroendocrine tumors. 13 However, theoretically, some point mutations might affect protein function without abolishing protein expression. Therefore, the immunostaining assay might underestimate the frequency of dysfunctional ATRX protein.…”

Section: Discussionmentioning

confidence: 99%

“…Heaphy et al discovered that alternative lengthening of telomeres status was perfectly correlated with the loss of expression of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein in pancreatic neuroendocrine tumors. 13 ATRX and DAXX form a dimer that acts as a histone chaperone to deposit histone variant H3.3 to GC-rich regions of the genome, including the telomeres, and plays important roles in maintaining telomere stability. [14][15][16] It is hypothesized that dysfunction of the dimer leads to telomere instability, increased telomere homologous recombination, and ultimately, alternative lengthening of telomeres.…”

mentioning

confidence: 99%

“…Subsequent studies have reported frequent ATRX loss (but not DAXX loss) in astrocytoma, leiomyosarcoma, dedifferentiated liposarcoma and other tumor types, and the loss of ATRX has been highly correlated with the alternative lengthening of telomeres phenotype. 6,12,13,[17][18][19][20][21] However, knockdown of ATRX or DAXX has not led to alternative lengthening of telomeres, and patients with germline ATRX mutations do not appear to be cancer prone. 18,22 In addition, although loss of either ATRX or DAXX is perfectly associated with alternative lengthening of telomeres in pancreatic neuroendocrine tumors, the situation is more complex in sarcomas.…”

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Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

et al. 2015

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According to cytogenetic aberrations, sarcomas can be categorized as complex or simple karyotype tumors. Alternative lengthening of telomeres is a telomere-maintenance mechanism common in sarcomas. Recently, this mechanism was found to be associated with loss of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. We previously reported that alternative lengthening of telomeres and loss of ATRX expression were common in leiomyosarcoma, angiosarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. In the present study, we screened an additional 245 sarcomas of other types to determine the prevalence of alternative lengthening of telomeres, loss of ATRX/DAXX expression, and their relationship. Undifferentiated pleomorphic sarcomas were frequently alternative lengthening of telomeres positive (65%) and loss of ATRX was seen in approximately half of the alternative lengthening of telomeres-positive tumors. Nineteen of 25 myxofibrosarcomas were alternative lengthening of telomerespositive, but only one was ATRX deficient. Three of 15 radiation-associated sarcomas were alternative lengthening of telomeres positive, but none of them was ATRX deficient. Alternative lengthening of telomeres and/or loss of ATRX were uncommon in malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, and embryonal rhabdomyosarcomas. By contrast, none of the 71 gene fusion-associated sarcomas was ATRX deficient or alternative lengthening of telomeres positive. All tumors exhibited preserved DAXX expression. Combining our previous studies and this study, a total of 384 sarcomas with complex karyotypes were examined, 83 of which were ATRX deficient (22%). By telomere-specific fluorescence in situ hybridization, 45% (138/308) were alternative lengthening of telomeres positive, 55% (76/138) of which were ATRX deficient. Loss of ATRX was highly associated with alternative lengthening of telomeres (Po 0.001). We conclude that alternative lengthening of telomeres is a frequent telomere-maintenance mechanism in cytogenetically complex sarcomas. Loss of ATRX is highly associated with this feature.

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confidence: 99%

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Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

et al. 2015

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“…Recent studies have also identified ATRX mutations in a number of cancers, including pancreatic neuroendocrine tumors and glioblastoma multiforme, suggesting that ATRX function is critically important to numerous aspect of cellular homeostasis (Heaphy et al, 2011;Schwartzentruber et al, 2012). Interestingly, Rett syndrome, a neurodevelopmental autism spectrum disorder caused by mutations in the MECP2 gene (Amir et al, 1999), has been indirectly linked to ATRX syndrome, although the direct functional consequences of disrupting ATRX/MeCP2 interactions in brain remain unclear.…”

Section: Atrx: a Critical Regulator Of Chromatin State And Histone Dymentioning

confidence: 99%

Histone Regulation in the CNS: Basic Principles of Epigenetic Plasticity

Maze

Noh

Allis

2012

Neuropsychopharmacol

115

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Postmitotic neurons are subject to a vast array of environmental influences that require the nuclear integration of intracellular signaling events to promote a wide variety of neuroplastic states associated with synaptic function, circuit formation, and behavioral memory. Over the last decade, much attention has been paid to the roles of transcription and chromatin regulation in guiding fundamental aspects of neuronal function. A great deal of this work has centered on neurodevelopmental and adulthood plasticity, with increased focus in the areas of neuropharmacology and molecular psychiatry. Here, we attempt to provide a broad overview of chromatin regulation, as it relates to central nervous system (CNS) function, with specific emphasis on the modes of histone posttranslational modifications, chromatin remodeling, and histone variant exchange. Understanding the functions of chromatin in the context of the CNS will aid in the future development of pharmacological therapeutics aimed at alleviating devastating neurological disorders.

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“…PanNETs with DAXX/ATRX mutations almost always have the ''alternative lengthening of telomeres'' (ALT?) phenotype [133,134]. Other genes targeted in PanNETs include genes coding for members of the phosphatidylinositol 3 0 -kinase (PI3K)-AKT-mTOR pathway.…”

Section: Pancreatic Neuroendocrine Tumorsmentioning

confidence: 99%

The genetic classification of pancreatic neoplasia

2015

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Cancer is caused by the accumulation of inherited and/or acquired alterations in specific genes. The recent decline in the cost of DNA sequencing has allowed tumor sequencing to be conducted on a large scale, which, in turn, has led to an unprecedented understanding of the genetic events that drive neoplasia. This understanding, when integrated with meticulous histologic analyses and with clinical findings, has direct clinical implications. The recent sequencing of all of the major types of cystic and noncystic neoplasms of the pancreas has revealed opportunities for molecular diagnoses and for personalized treatment. This review summarizes the results from these recent studies focusing on the clinical relevance of genomic data.

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Altered Telomeres in Tumors with ATRX and DAXX Mutations

Abstract: Chromosome tips seem to be maintained by an unusual mechanism in tumors that have mutations in chromatin remodeling genes.

Cited by 922 publications

References 21 publications

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

Histone Regulation in the CNS: Basic Principles of Epigenetic Plasticity

The genetic classification of pancreatic neoplasia

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