Skip to main content
Log in

New Genetics and Genomic Data on Pancreatic Neuroendocrine Tumors: Implications for Diagnosis, Treatment, and Targeted Therapies

  • Published:
Endocrine Pathology Aims and scope Submit manuscript

Abstract

The recent findings on the roles of death-associated protein 6/α-thalassemia/mental retardation X-linked (DAXX/ATRX) in the development of pancreatic neuroendocrine tumors (PanNETs) have led to major advances in the molecular understanding of these rare tumors and open up completely new therapeutic windows. This overview aims at giving a simplified view on these findings and their possible therapeutic implications. The importance of epigenetic changes in PanNET is also underlined by recent findings of a cross-species study on microRNA (miRNA) and messenger RNA (mRNA) profiles in PanNETs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Halfdanarson TR, Rubin J, Farnell MB et al. (2008) Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors. Endocr Relat Cancer 15(2):409–427

    Article  PubMed  PubMed Central  Google Scholar 

  2. Jiao Y, Shi C, Edil BH et al (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331(6021):1199–1203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Marinoni I, Kurrer AS, Vassella E et al. (2014) Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology 146(2):453–460 e5

  4. Heaphy CM, de Wilde RF, Jiao Y et al. (2011) Altered telomeres in tumors with ATRX and DAXX mutations. Science 333(6041):425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Maze I, Noh KM Allis CD (2013) Histone regulation in the CNS: basic principles of epigenetic plasticity. Neuropsychopharmacology 38(1):3–22

    Article  CAS  PubMed  Google Scholar 

  6. Jonkers YM, Claessen SM, Perren A et al. (2005) Chromosomal instability predicts metastatic disease in patients with insulinomas. Endocr Relat Cancer 12(2):435–447

    Article  CAS  PubMed  Google Scholar 

  7. Zhao J, Moch H, Scheidweiler AF et al. (2001) Genomic imbalances in the progression of endocrine pancreatic tumors. Genes Chromosomes Cancer 32(4):364–372

    Article  CAS  PubMed  Google Scholar 

  8. Kong CM, Lee XW Wang X (2013) Telomere shortening in human diseases. FEBS J 280(14):3180–3193

    Article  CAS  PubMed  Google Scholar 

  9. Anlauf M, Enosawa T, Henopp T et al. (2008) Primary lymph node gastrinoma or occult duodenal microgastrinoma with lymph node metastases in a MEN1 patient: the need for a systematic search for the primary tumor. Am J Surg Pathol 32(7):1101–1105

    Article  PubMed  Google Scholar 

  10. de Wilde RF, Heaphy CM, Maitra A et al. (2012) Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors. Mod Pathol 25(7):1033–1039

    Article  PubMed  PubMed Central  Google Scholar 

  11. Puto LA Reed JC (2008) Daxx represses RelB target promoters via DNA methyltransferase recruitment and DNA hypermethylation. Genes Dev 22(8):998–1010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Meissner A, Mikkelsen TS, Gu H et al. (2008) Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454(7205):766–770

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Pipinikas CP, Dibra H, Karpathakis A et al. (2015) Epigenetic dysregulation and poorer prognosis in DAXX-deficient pancreatic neuroendocrine tumours. Endocr Relat Cancer 22(3):L13–L18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Stefanoli M, La Rosa S, Sahnane N et al. (2014) Prognostic relevance of aberrant DNA methylation in g1 and g2 pancreatic neuroendocrine tumors. Neuroendocrinology 100(1):26–34

    Article  CAS  PubMed  Google Scholar 

  15. Flynn RL, Cox KE, Jeitany Met al. (2015) Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science 347(6219):273–277

  16. Juo YY, Gong XJ, Mishra A et al. (2015) Epigenetic therapy for solid tumors: from bench science to clinical trials. Epigenomics 7(2):215–235

    Article  CAS  PubMed  Google Scholar 

  17. Zahnow CA, Topper M, Stone M et al. (2016) Inhibitors of DNA Methylation, Histone Deacetylation, and Histone Demethylation: A Perfect Combination for Cancer Therapy. Adv Cancer Res 130:55–111

    Article  CAS  PubMed  Google Scholar 

  18. Sadanandam A, Wullschleger S, Lyssiotis CA et al. (2015) A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics. Cancer Discov 5(12):1296–1313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anja M. Schmitt.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schmitt, A.M., Marinoni, I., Blank, A. et al. New Genetics and Genomic Data on Pancreatic Neuroendocrine Tumors: Implications for Diagnosis, Treatment, and Targeted Therapies. Endocr Pathol 27, 200–204 (2016). https://doi.org/10.1007/s12022-016-9447-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12022-016-9447-2

Keywords

Navigation