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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} (N.P.); rhruban{at} (R.H.H.); kinzlke{at} (K.W.K.)

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