Altered Telomeres in Tumors with ATRX and DAXX Mutations

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

doi:10.1126/science.1207313

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Altered Telomeres in Tumors with ATRX and DAXX Mutations

Christopher M. Heaphy¹,*,†,
Roeland F. de Wilde¹,*,
Yuchen Jiao²,*,
Alison P. Klein¹,³,⁴,
Barish H. Edil³,
Chanjuan Shi⁵,
Chetan Bettegowda²,⁶,
Fausto J. Rodriguez¹,
Charles G. Eberhart¹,
Sachidanand Hebbar¹,
G. Johan Offerhaus⁷,
Roger McLendon⁸,
B. Ahmed Rasheed⁸,
Yiping He⁸,
Hai Yan⁸,
Darell D. Bigner⁸,
Sueli Mieko Oba-Shinjo⁹,
Suely Kazue Nagahashi Marie⁹,
Gregory J. Riggins⁶,
Kenneth W. Kinzler²,
Bert Vogelstein²,
Ralph H. Hruban¹,³,
Anirban Maitra¹,³,
Nickolas Papadopoulos²,‡,
Alan K. Meeker¹,³,‡

¹Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
²Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
³Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
⁴Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21231, USA.
⁵Department of Pathology, Vanderbilt University, Nashville, TN 37240, USA.
⁶Department of Neurosurgery, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
⁷Department of Pathology, University Medical Center Utrecht, xxxx Utrecht, Netherlands.
⁸Preston Rober Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute and Department of Pathology, Duke University Medical Center, Durham, NC xxxxx, USA.
⁹Department of Neurology, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.

↵‡To whom correspondence should be addressed. E-mail: ameeker1{at}jhmi.edu (A.K.M.); npapado1{at}jhmi.edu (N.P.)

↵* These authors contributed equally to this work.

↵† The list of all affiliations is available in the supporting online material.

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Science 22 Jul 2011:
Vol. 333, Issue 6041, pp. 425
DOI: 10.1126/science.1207313

Christopher M. Heaphy

1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

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Roeland F. de Wilde

1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

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Yuchen Jiao

2Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.

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Alison P. Klein

1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

3Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

4Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21231, USA.

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Barish H. Edil

3Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

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Chanjuan Shi

5Department of Pathology, Vanderbilt University, Nashville, TN 37240, USA.

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Chetan Bettegowda

2Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.

6Department of Neurosurgery, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

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Fausto J. Rodriguez

1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

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Charles G. Eberhart

1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

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Sachidanand Hebbar

1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

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G. Johan Offerhaus

7Department of Pathology, University Medical Center Utrecht, xxxx Utrecht, Netherlands.

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Roger McLendon

8Preston Rober Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute and Department of Pathology, Duke University Medical Center, Durham, NC xxxxx, USA.

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B. Ahmed Rasheed

8Preston Rober Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute and Department of Pathology, Duke University Medical Center, Durham, NC xxxxx, USA.

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Yiping He

8Preston Rober Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute and Department of Pathology, Duke University Medical Center, Durham, NC xxxxx, USA.

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Hai Yan

8Preston Rober Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute and Department of Pathology, Duke University Medical Center, Durham, NC xxxxx, USA.

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Darell D. Bigner

8Preston Rober Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute and Department of Pathology, Duke University Medical Center, Durham, NC xxxxx, USA.

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Sueli Mieko Oba-Shinjo

9Department of Neurology, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.

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Suely Kazue Nagahashi Marie

9Department of Neurology, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.

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Gregory J. Riggins

6Department of Neurosurgery, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

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Kenneth W. Kinzler

2Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.

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Bert Vogelstein

2Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.

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Ralph H. Hruban

1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

3Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

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Anirban Maitra

1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

3Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

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Nickolas Papadopoulos

2Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.

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For correspondence: ameeker1@jhmi.edu npapado1@jhmi.edu

Alan K. Meeker

1Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

3Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

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For correspondence: ameeker1@jhmi.edu npapado1@jhmi.edu

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Abstract

The proteins encoded by ATRX and DAXX participate in chromatin remodeling at telomeres and other genomic sites. Because inactivating mutations of these genes are common in human pancreatic neuroendocrine tumors (PanNETs), we examined the telomere status of these tumors. We found that 61% of PanNETs displayed abnormal telomeres that are characteristic of a telomerase-independent telomere maintenance mechanism termed ALT (alternative lengthening of telomeres). All of the PanNETs exhibiting these abnormal telomeres had ATRX or DAXX mutations or loss of nuclear ATRX or DAXX protein. ATRX mutations also correlate with abnormal telomeres in tumors of the central nervous system. These data suggest that an alternative telomere maintenance function may operate in human tumors with alterations in the ATRX or DAXX genes.

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Altered Telomeres in Tumors with ATRX and DAXX Mutations

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