Science · 2011 · 1.7K citations · 23 references
MedicineGeneticsOncologyCancer GeneticsMolecular OncologyNeoplasiaCancer EpigeneticsCancer GenomicsChromatinEndocrine Tumor GeneticsEpigenetic Alterations In CancerPancreatic CancerChromatin RemodelingChromatin Remodeling Gene AlterationsMen1 Gene AlterationsMen1 Gene MutationsMtor InhibitionMtor SignalingPancreatic Neuroendocrine Tumor GeneticsSomatic Mutations
Pancreatic neuroendocrine tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. The study aimed to investigate the genetic basis of PanNETs by sequencing exomes of 10 nonfamilial tumors and screening common mutations in 58 additional cases. Exomic sequencing of 10 nonfamilial PanNETs was performed, followed by targeted screening of frequently mutated genes in 58 further tumors. Somatic inactivating mutations in MEN1 (44%) and DAXX/ATRX (43%) were most common, correlated with better prognosis, and 14% of tumors harbored mTOR pathway mutations that could guide mTOR inhibitor therapy.
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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