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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U2 - 10.1126/science.1200609
DO - 10.1126/science.1200609
M3 - Article
C2 - 21252315
AN - SCOPUS:79952279828
SN - 0036-8075
VL - 331
SP - 1199
EP - 1203
JO - Science
JF - Science
IS - 6021
ER -