DAXX/ATRX, MEN1 and mTOR Pathway Genes are Frequently Altered in Pancreatic Neuroendocrine Tumors

By Y. Jiao, C. Shi, B. Edil, R. D. de Wilde, D. Klimstra, A. Maitra, R. Schulick, Laura H. Tang, elliot k fishman, M. Choti and 6 more. Science, 2011

1,673 citations recorded by the source corpus.

A rare but deadly form of human pancreatic cancer harbors mutations in chromatin remodeling genes. 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.

Subfields: Epidemiology, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/07fedce5c2afdce7c4f8741b5980ec4502970f5f

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In Epidemiology

1. Mark Schiffman
2. M. Stanley

In Molecular Biology

1. L. Diaz
2. Victor E. Velculescu
3. Bert Vogelstein
4. Kenneth W. Kinzler
5. M. Dawson
6. Rajiv K. Tonk
7. Tony Kouzarides
8. Vivek Panwar

Citations in the corpus

• Pathology and Genetics (2010, background): “Mutations in oncogenes are never or rarely observed in PanNENs [31, 32].”
• Signatures of mutational processes in human cancer (2013, neutral): “In these cancers the mutation characteristics were different (SupplementaryFig.98),bearingthehallmarksofsomatichypermutation associatedwithAID,whichisoperativeduringthegenerationof immunologicaldiversity 20 .”
• Cancer epigenetics: from mechanism to therapy. (2012, background): “The ATRX/DAXX mutations described here are also a seminal feature of pancreatic neuroendocrine tumors (Jiao et al., 2011) and highlight emerging evidence suggesting that mutations in members of chromatin-remodeling complexes are a common feature in human malignancy.”
• Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “80 Another study has revealed that mRNAs that are controlled by mTORC1 are 5 ’ terminal oligopyrimidine (TOP) motifs.”