Journal
SCIENCE
Volume 331, Issue 6021, Pages 1199-1203Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1200609
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Funding
- Caring for Carcinoid Foundation
- Lustgarten Foundation for Pancreatic Cancer Research
- Sol Goldman Pancreatic Cancer Research Center
- Joseph L. Rabinowitz Fund for Pancreatic Cancer Research
- Virginia and D. K. Ludwig Fund for Cancer Research
- Raymond and Beverly Sackler Research Foundation
- American Associatoion for Cancer Research
- National Institutes of Health [CA121113, P50CA062924, P01CA134292, R01CA113669]
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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 (alpha 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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