DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors.
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.
Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
Yuchen
Y
Jiao
Chanjuan
C
Shi
Barish H
BH
Edil
Roeland F
RF
de Wilde
David S
DS
Klimstra
Anirban
A
Maitra
Richard D
RD
Schulick
Laura H
LH
Tang
Christopher L
CL
Wolfgang
Michael A
MA
Choti
Victor E
VE
Velculescu
Luis A
LA
Diaz
Bert
B
Vogelstein
Kenneth W
KW
Kinzler
Ralph H
RH
Hruban
Nickolas
N
Papadopoulos
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D056970:Co-Repressor Proteins; D004265:DNA Helicases / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006801:Humans; D018832:Molecular Chaperones; D009154:Mutation; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000075924:X-linked Nuclear Protein
D048868:Adaptor Proteins, Signal Transducing; D058534:Class I Phosphatidylinositol 3-Kinases; D056970:Co-Repressor Proteins; D004265:DNA Helicases; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000075924:X-linked Nuclear Protein; C106985:DAXX protein, human; C105373:MEN1 protein, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C494929:PTEN protein, human; C092332:ATRX protein, human
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