DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors

Yuchen Jiao; Chanjuan Shi; Barish H Edil; Roeland F de Wilde; David S Klimstra; Anirban Maitra; Richard D Schulick; Laura H Tang; Christopher L Wolfgang; Michael A Choti; Victor E Velculescu; Luis A Diaz; Bert Vogelstein; Kenneth W Kinzler; Ralph H Hruban; Nickolas Papadopoulos

doi:10.1126/science.1200609

DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors

Yuchen Jiao, Chanjuan Shi, Barish H Edil, Roeland F de Wilde, David S Klimstra, Anirban Maitra, Richard D Schulick, Laura H Tang, Christopher L Wolfgang, Michael A Choti, Victor E Velculescu, Luis A Diaz, Bert Vogelstein, Kenneth W Kinzler, Ralph H Hruban, Nickolas Papadopoulos

Research output: Contribution to journal › Article › Academic › peer-review

1424 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1199-203
Number of pages	5
Journal	Science (New York, N.Y.)
Volume	331
Issue number	6021
DOIs	https://doi.org/10.1126/science.1200609
Publication status	Published - 4 Mar 2011
Externally published	Yes

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Jiao, Y., Shi, C., Edil, B. H., de Wilde, R. F., Klimstra, D. S., Maitra, A., Schulick, R. D., Tang, L. H., Wolfgang, C. L., Choti, M. A., Velculescu, V. E., Diaz, L. A., Vogelstein, B., Kinzler, K. W., Hruban, R. H., & Papadopoulos, N. (2011). DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science (New York, N.Y.), 331(6021), 1199-203. https://doi.org/10.1126/science.1200609

@article{595111cc27ba488692108b317ada2f49,

title = "DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors",

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.",

author = "Yuchen Jiao and Chanjuan Shi and Edil, {Barish H} and {de Wilde}, {Roeland F} and Klimstra, {David S} and Anirban Maitra and Schulick, {Richard D} and Tang, {Laura H} and Wolfgang, {Christopher L} and Choti, {Michael A} and Velculescu, {Victor E} and Diaz, {Luis A} and Bert Vogelstein and Kinzler, {Kenneth W} and Hruban, {Ralph H} and Nickolas Papadopoulos",

year = "2011",

month = mar,

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doi = "10.1126/science.1200609",

language = "English",

volume = "331",

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Jiao, Y, Shi, C, Edil, BH, de Wilde, RF, Klimstra, DS, Maitra, A, Schulick, RD, Tang, LH, Wolfgang, CL, Choti, MA, Velculescu, VE, Diaz, LA, Vogelstein, B, Kinzler, KW, Hruban, RH & Papadopoulos, N 2011, 'DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors', Science (New York, N.Y.), vol. 331, no. 6021, pp. 1199-203. https://doi.org/10.1126/science.1200609

TY - JOUR

T1 - DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors

AU - Jiao, Yuchen

AU - Shi, Chanjuan

AU - Edil, Barish H

AU - de Wilde, Roeland F

AU - Klimstra, David S

AU - Maitra, Anirban

AU - Schulick, Richard D

AU - Tang, Laura H

AU - Wolfgang, Christopher L

AU - Choti, Michael A

AU - Velculescu, Victor E

AU - Diaz, Luis A

AU - Vogelstein, Bert

AU - Kinzler, Kenneth W

AU - Hruban, Ralph H

AU - Papadopoulos, Nickolas

PY - 2011/3/4

Y1 - 2011/3/4

N2 - 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.

AB - 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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DO - 10.1126/science.1200609

M3 - Article

C2 - 21252315

SN - 0036-8075

VL - 331

SP - 1199

EP - 1203

JO - Science (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 6021

ER -

DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors

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