Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 331 (6021): 1199-1203

Copyright © 2011 by the American Association for the Advancement of Science

DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors

Yuchen Jiao,1,* Chanjuan Shi,2,* Barish H. Edil,3 Roeland F. de Wilde,2 David S. Klimstra,4 Anirban Maitra,5 Richard D. Schulick,3 Laura H. Tang,4 Christopher L. Wolfgang,3 Michael A. Choti,3 Victor E. Velculescu,1 Luis A. Diaz, Jr.,1,6 Bert Vogelstein,1 Kenneth W. Kinzler,1,{dagger} Ralph H. Hruban,5,{dagger} Nickolas Papadopoulos1,{dagger}

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.

1 Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
2 Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
3 Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
4 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
5 Departments of Pathology and Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
6 Swim Across America Laboratory, Johns Hopkins University, Baltimore, MD 21231, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: npapado1{at}jhmi.edu (N.P.); rhruban{at}jhmi.edu (R.H.H.); kinzlke{at}jhmi.edu (K.W.K.)

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
A multi-institutional, phase II open-label study of ganitumab (AMG 479) in advanced carcinoid and pancreatic neuroendocrine tumors.
J. R. Strosberg, J. A. Chan, D. P. Ryan, J. A. Meyerhardt, C. S. Fuchs, T. Abrams, E. Regan, R. Brady, J. Weber, T. Campos, et al. (2013)
Endocr. Relat. Cancer 20, 383-390
   Abstract »    Full Text »    PDF »
Neuroendocrine tumours: cracking the epigenetic code.
A. Karpathakis, H. Dibra, and C. Thirlwell (2013)
Endocr. Relat. Cancer 20, R65-R82
   Abstract »    Full Text »    PDF »
Sp100A promotes chromatin decondensation at a cytomegalovirus-promoter-regulated transcription site.
A. Newhart, D. G. Negorev, I. U. Rafalska-Metcalf, T. Yang, G. G. Maul, and S. M. Janicki (2013)
Mol. Biol. Cell 24, 1454-1468
   Abstract »    Full Text »    PDF »
Laser capture microdissection-reduced representation bisulfite sequencing (LCM-RRBS) maps changes in DNA methylation associated with gonadectomy-induced adrenocortical neoplasia in the mouse.
M. Schillebeeckx, A. Schrade, A.-K. Lobs, M. Pihlajoki, D. B. Wilson, and R. D. Mitra (2013)
Nucleic Acids Res.
   Abstract »    Full Text »    PDF »
Menin Epigenetically Represses Hedgehog Signaling in MEN1 Tumor Syndrome.
B. Gurung, Z. Feng, D. V. Iwamoto, A. Thiel, G. Jin, C.-M. Fan, J. M. Y. Ng, T. Curran, and X. Hua (2013)
Cancer Res. 73, 2650-2658
   Abstract »    Full Text »    PDF »
TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal.
P. J. Killela, Z. J. Reitman, Y. Jiao, C. Bettegowda, N. Agrawal, L. A. Diaz Jr., A. H. Friedman, H. Friedman, G. L. Gallia, B. C. Giovanella, et al. (2013)
PNAS 110, 6021-6026
   Abstract »    Full Text »    PDF »
PML bodies provide an important platform for the maintenance of telomeric chromatin integrity in embryonic stem cells.
F. T. M. Chang, J. D. McGhie, F. L. Chan, M. C. Tang, M. A. Anderson, J. R. Mann, K. H. Andy Choo, and L. H. Wong (2013)
Nucleic Acids Res. 41, 4447-4458
   Abstract »    Full Text »    PDF »
Whole-Exome Sequencing Studies of Nonfunctioning Pituitary Adenomas.
P. J. Newey, M. A. Nesbit, A. J. Rimmer, R. A. Head, C. M. Gorvin, M. Attar, L. Gregory, J. A. H. Wass, D. Buck, N. Karavitaki, et al. (2013)
J. Clin. Endocrinol. Metab. 98, E796-E800
   Abstract »    Full Text »    PDF »
Cancer Genome Landscapes.
B. Vogelstein, N. Papadopoulos, V. E. Velculescu, S. Zhou, L. A. Diaz Jr., and K. W. Kinzler (2013)
Science 339, 1546-1558
   Abstract »    Full Text »    PDF »
Everolimus in Advanced Pancreatic Neuroendocrine Tumors: The Clinical Experience.
J. C. Yao, A. T. Phan, V. Jehl, G. Shah, and F. Meric-Bernstam (2013)
Cancer Res. 73, 1449-1453
   Abstract »    Full Text »    PDF »
The embryonic transcription factor Hlxb9 is a menin interacting partner that controls pancreatic {beta}-cell proliferation and the expression of insulin regulators.
K. Shi, V. I. Parekh, S. Roy, S. S. Desai, and S. K. Agarwal (2013)
Endocr. Relat. Cancer 20, 111-122
   Abstract »    Full Text »    PDF »
Are Neuroendocrine Tumors Going Mainstream?.
M. H. Kulke (2013)
J. Clin. Oncol. 31, 404-405
   Full Text »    PDF »
Methylation of RASSF1A gene promoter is regulated by p53 and DAXX.
H. Zhang, J. He, J. Li, D. Tian, L. Gu, and M. Zhou (2013)
FASEB J 27, 232-242
   Abstract »    Full Text »    PDF »
Single-cell analysis of Daxx and ATRX-dependent transcriptional repression.
A. Newhart, I. U. Rafalska-Metcalf, T. Yang, D. G. Negorev, and S. M. Janicki (2012)
J. Cell Sci. 125, 5489-5501
   Abstract »    Full Text »    PDF »
Proliferation Rates of Multiple Endocrine Neoplasia Type 1 (MEN1)-Associated Tumors.
G. V. Walls, A. A. C. Reed, J. Jeyabalan, M. Javid, N. R. Hill, B. Harding, and R. V. Thakker (2012)
Endocrinology 153, 5167-5179
   Abstract »    Full Text »    PDF »
Whole-Exome Sequencing Studies of Nonhereditary (Sporadic) Parathyroid Adenomas.
P. J. Newey, M. A. Nesbit, A. J. Rimmer, M. Attar, R. T. Head, P. T. Christie, C. M. Gorvin, M. Stechman, L. Gregory, R. Mihai, et al. (2012)
J. Clin. Endocrinol. Metab. 97, E1995-E2005
   Abstract »    Full Text »    PDF »
{alpha}-Thalassemia, Mental Retardation, and Myelodysplastic Syndrome.
R. J. Gibbons (2012)
Cold Spring Harb Perspect Med 2, a011759
   Abstract »    Full Text »    PDF »
Neuroendocrine tumor disease: an evolving landscape.
A. Frilling, G. Akerstrom, M. Falconi, M. Pavel, J. Ramos, M. Kidd, and I. M. Modlin (2012)
Endocr. Relat. Cancer 19, R163-R185
   Abstract »    Full Text »    PDF »
Personal and population genomics of human regulatory variation.
B. Vernot, A. B. Stergachis, M. T. Maurano, J. Vierstra, S. Neph, R. E. Thurman, J. A. Stamatoyannopoulos, and J. M. Akey (2012)
Genome Res. 22, 1689-1697
   Abstract »    Full Text »    PDF »
Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1).
R. V. Thakker, P. J. Newey, G. V. Walls, J. Bilezikian, H. Dralle, P. R. Ebeling, S. Melmed, A. Sakurai, F. Tonelli, and M. L. Brandi (2012)
J. Clin. Endocrinol. Metab. 97, 2990-3011
   Abstract »    Full Text »    PDF »
Attenuation of the Retinoblastoma Pathway in Pancreatic Neuroendocrine Tumors Due to Increased Cdk4/Cdk6.
L. H. Tang, T. Contractor, R. Clausen, D. S. Klimstra, Y.-C. N. Du, P. J. Allen, M. F. Brennan, A. J. Levine, and C. R. Harris (2012)
Clin. Cancer Res. 18, 4612-4620
   Abstract »    Full Text »    PDF »
Molecular markers in pediatric neuro-oncology.
K. Ichimura, R. Nishikawa, and M. Matsutani (2012)
Neuro Oncology 14, iv90-iv99
   Abstract »    Full Text »    PDF »
Genetic Basis of Pancreas Cancer Development and Progression: Insights from Whole-Exome and Whole-Genome Sequencing.
C. A. Iacobuzio-Donahue, V. E. Velculescu, C. L. Wolfgang, and R. H. Hruban (2012)
Clin. Cancer Res. 18, 4257-4265
   Abstract »    Full Text »    PDF »
FDA Approval Summary: Sunitinib for the Treatment of Progressive Well-Differentiated Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors.
G. M. Blumenthal, P. Cortazar, J. J. Zhang, S. Tang, R. Sridhara, A. Murgo, R. Justice, and R. Pazdur (2012)
Oncologist 17, 1108-1113
   Abstract »    Full Text »    PDF »
Reproducible Quantification of Cancer-Associated Proteins in Body Fluids Using Targeted Proteomics.
R. Huttenhain, M. Soste, N. Selevsek, H. Rost, A. Sethi, C. Carapito, T. Farrah, E. W. Deutsch, U. Kusebauch, R. L. Moritz, et al. (2012)
Science Translational Medicine 4, 142ra94
   Abstract »    Full Text »    PDF »
Genetic evolution of pancreatic cancer: lessons learnt from the pancreatic cancer genome sequencing project.
C. A. Iacobuzio-Donahue (2012)
Gut 61, 1085-1094
   Abstract »    Full Text »    PDF »
Key Principles and Clinical Applications of "Next-Generation" DNA Sequencing.
J. M. Rizzo and M. J. Buck (2012)
Cancer Prevention Research 5, 887-900
   Abstract »    Full Text »    PDF »
Molecular pathology and genetics of pancreatic endocrine tumours.
G. Capurso, S. Festa, R. Valente, M. Piciucchi, F. Panzuto, R. T. Jensen, and G. Delle Fave (2012)
J. Mol. Endocrinol. 49, R37-R50
   Abstract »    Full Text »    PDF »
Systemic Therapy for Advanced Pancreatic Neuroendocrine Tumors: An Update.
D. L. Reidy-Lagunes (2012)
J Natl Compr Canc Netw 10, 777-783
   Abstract »    Full Text »    PDF »
Systemic Therapy for Advanced Carcinoid Tumors: Where Do We Go From Here?.
A. S. Paulson and E. K. Bergsland (2012)
J Natl Compr Canc Netw 10, 785-793
   Abstract »    Full Text »    PDF »
Hitting the target: where do molecularly targeted therapies fit in the treatment scheduling of neuroendocrine tumours?.
A. Karpathakis, M. Caplin, and C. Thirlwell (2012)
Endocr. Relat. Cancer 19, R73-R92
   Abstract »    Full Text »    PDF »
Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma.
K. M. Mann, J. M. Ward, C. C. K. Yew, A. Kovochich, D. W. Dawson, M. A. Black, B. T. Brett, T. E. Sheetz, A. J. Dupuy, Australian Pancreatic Cancer Genome Initiative, et al. (2012)
PNAS 109, 5934-5941
   Abstract »    Full Text »    PDF »
New Strategies for Advanced Neuroendocrine Tumors in the Era of Targeted Therapy.
M. Dong, A. T. Phan, and J. C. Yao (2012)
Clin. Cancer Res. 18, 1830-1836
   Abstract »    Full Text »    PDF »
PIK3CA/PTEN Mutations and Akt Activation As Markers of Sensitivity to Allosteric mTOR Inhibitors.
F. Meric-Bernstam, A. Akcakanat, H. Chen, K.-A. Do, T. Sangai, F. Adkins, A. M. Gonzalez-Angulo, A. Rashid, K. Crosby, M. Dong, et al. (2012)
Clin. Cancer Res. 18, 1777-1789
   Abstract »    Full Text »    PDF »
A New Era for the Systemic Therapy of Neuroendocrine Tumors.
J. R. Eads and N. J. Meropol (2012)
Oncologist 17, 326-338
   Abstract »    Full Text »    PDF »
Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer.
G. C. Hon, R. D. Hawkins, O. L. Caballero, C. Lo, R. Lister, M. Pelizzola, A. Valsesia, Z. Ye, S. Kuan, L. E. Edsall, et al. (2012)
Genome Res. 22, 246-258
   Abstract »    Full Text »    PDF »
ATM Mutations in Patients with Hereditary Pancreatic Cancer.
N. J. Roberts, Y. Jiao, J. Yu, L. Kopelovich, G. M. Petersen, M. L. Bondy, S. Gallinger, A. G. Schwartz, S. Syngal, M. L. Cote, et al. (2012)
Cancer Discovery 2, 41-46
   Abstract »    Full Text »    PDF »
Network of Cancer Genes (NCG 3.0): integration and analysis of genetic and network properties of cancer genes.
M. D'Antonio, V. Pendino, S. Sinha, and F. D. Ciccarelli (2012)
Nucleic Acids Res. 40, D978-D983
   Abstract »    Full Text »    PDF »
Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways.
J. Wu, Y. Jiao, M. Dal Molin, A. Maitra, R. F. de Wilde, L. D. Wood, J. R. Eshleman, M. G. Goggins, C. L. Wolfgang, M. I. Canto, et al. (2011)
PNAS 108, 21188-21193
   Abstract »    Full Text »    PDF »
Chromogranin A and Neuron-Specific Enolase as Prognostic Markers in Patients with Advanced pNET Treated with Everolimus.
J. C. Yao, M. Pavel, A. T. Phan, M. H. Kulke, S. Hoosen, J. St. Peter, A. Cherfi, and K. E. Oberg (2011)
J. Clin. Endocrinol. Metab. 96, 3741-3749
   Abstract »    Full Text »    PDF »
Improved Control of Severe Hypoglycemia in Patients with Malignant Insulinomas by Peptide Receptor Radionuclide Therapy.
E. van Schaik, E. I. van Vliet, R. A. Feelders, E. P. Krenning, S. Khan, K. Kamp, R. Valkema, F. H. van Nederveen, J. J. M. Teunissen, D. J. Kwekkeboom, et al. (2011)
J. Clin. Endocrinol. Metab. 96, 3381-3389
   Abstract »    Full Text »    PDF »
Mutations in CIC and FUBP1 Contribute to Human Oligodendroglioma.
C. Bettegowda, N. Agrawal, Y. Jiao, M. Sausen, L. D. Wood, R. H. Hruban, F. J. Rodriguez, D. P. Cahill, R. McLendon, G. Riggins, et al. (2011)
Science 333, 1453-1455
   Abstract »    Full Text »    PDF »
Understanding the Enemy.
V. E. Velculescu and L. A. Diaz Jr. (2011)
Science Translational Medicine 3, 98ps37
   Full Text »    PDF »
Src kinase activity coordinates cell adhesion and spreading with activation of mammalian target of rapamycin in pancreatic endocrine tumour cells.
A. Di Florio, L. Adesso, S. Pedrotti, G. Capurso, E. Pilozzi, V. Corbo, A. Scarpa, R. Geremia, G. Delle Fave, and C. Sette (2011)
Endocr. Relat. Cancer 18, 541-554
   Abstract »    Full Text »    PDF »
Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1.
N. Agrawal, M. J. Frederick, C. R. Pickering, C. Bettegowda, K. Chang, R. J. Li, C. Fakhry, T.-X. Xie, J. Zhang, J. Wang, et al. (2011)
Science 333, 1154-1157
   Abstract »    Full Text »    PDF »
A Shining Light in the Darkness for the Treatment of Pancreatic Neuroendocrine Tumors.
J. Capdevila and J. Tabernero (2011)
Cancer Discovery 1, 213-221
   Abstract »    Full Text »    PDF »
Role of ATRX in chromatin structure and function: implications for chromosome instability and human disease.
R. De La Fuente, C. Baumann, and M. M. Viveiros (2011)
Reproduction 142, 221-234
   Abstract »    Full Text »    PDF »
Altered Telomeres in Tumors with ATRX and DAXX Mutations.
C. M. Heaphy, R. F. de Wilde, Y. Jiao, A. P. Klein, B. H. Edil, C. Shi, C. Bettegowda, F. J. Rodriguez, C. G. Eberhart, S. Hebbar, et al. (2011)
Science 333, 425
   Abstract »    Full Text »    PDF »
Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d'etude des Tumeurs Endocrines.
P. Goudet, C. Bonithon-Kopp, A. Murat, P. Ruszniewski, P. Niccoli, F. Menegaux, G. Chabrier, F. Borson-Chazot, A. Tabarin, P. Bouchard, et al. (2011)
Eur. J. Endocrinol. 165, 97-105
   Abstract »    Full Text »    PDF »
The Death of the Cancer Cell.
C. Sonnenschein and A. M. Soto (2011)
Cancer Res. 71, 4334-4337
   Abstract »    Full Text »    PDF »
New Epigenetic Drivers of Cancers.
S. J. Elsasser, C. D. Allis, and P. W. Lewis (2011)
Science 331, 1145-1146
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882