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  • Review Article
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Well-differentiated pancreatic neuroendocrine tumors: from genetics to therapy

Nature Reviews Gastroenterology & Hepatology volume 9, pages 199–208 (2012)Cite this article

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Abstract

Well-differentiated pancreatic neuroendocrine tumors (PanNETs) comprise ∼1–3% of pancreatic neoplasms. Although long considered as reasonably benign lesions, PanNETs have considerable malignant potential, with a 5-year survival of ∼65% and a 10-year survival of 45% for resected lesions. As PanNETs have a low incidence, they have been understudied, with few advances made until the completion of their exomic sequencing in the past year. In this Review, we summarize some of the latest insights into the genetics of PanNETs, and their probable implications in the context of prognosis and therapy. In particular, we discuss two genes (DAXX and ATRX) that have collectively been identified as mutated in >40% of PanNETs, and the biological and prognostic implications of these novel mutations. The identification of recurrent somatic mutations within the mTOR signaling pathway and the therapeutic implications for personalized therapy in patients with PanNETs are also discussed. Finally, this Review outlines state-of-the-art advances in the biology of PanNETs that are of emerging translational importance.

Key Points

  • Pancreatic neuroendocrine tumors (PanNETs) are fully malignant neoplasms, with the majority (∼70%) of patients presenting with advanced disease and a 5-year survival of ∼65%

  • In 2010, the WHO implemented a new classification for PanNETs that stratifies these tumors by stage and histological grade (the latter defined by mitotic counts or Ki-67 labeling index)

  • Sequencing of the PanNET exome has identified somatic mutations in MEN1, DAXX, ATRX and mTOR pathway genes in 44%, 25%, 18% and ∼16% of PanNETs, respectively

  • ATRX and DAXX are PanNET tumor suppressor genes that are involved in chromatin remodeling—mutations in these genes are correlated with the alternative lengthening of telomeres phenotype

  • Two molecularly targeted therapies—sunitinib (VEGF inhibitor) and everolimus (mTOR inhibitor)—have been independently shown to improve progression-free survival in patients with metastatic PanNETs, and are approved by the FDA

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Figure 1: Gross appearance and histologic features of well-differentiated pancreatic neuroendocrine tumors (PanNETs).
Figure 2: The mTOR signaling pathway.
Figure 3: Loss of ATRX or DAXX function in pancreatic neuroendocrine tumors (PanNETs) correlates with the alternative lengthening of telomeres (ALT) phenotype.

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Acknowledgements

The authors would like to acknowledge the support of the Sol Goldman Pancreatic Cancer Research Center and the Caring for Carcinoid Foundation. The authors are grateful to Drs Alan Meeker and Christopher Heaphy (Johns Hopkins University) for assistance with Figure 3 of this Review and helpful suggestions.

Author information

Authors and Affiliations

  1. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, 1550 Orleans Street Baltimore, MD 21231, USA,

    Roeland F. de Wilde, Ralph H. Hruban & Anirban Maitra

  2. Department of Surgery, The Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, 21231, MD, USA

    Barish H. Edil

Authors
  1. Roeland F. de Wilde
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  2. Barish H. Edil
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  3. Ralph H. Hruban
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  4. Anirban Maitra
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Contributions

R. F. de Wilde and A. Maitra researched data for the article. All authors contributed equally to discussion of the content, writing the manuscript and reviewing/editing the manuscript before submission.

Corresponding author

Correspondence to Anirban Maitra.

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The authors declare no competing financial interests.

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de Wilde, R., Edil, B., Hruban, R. et al. Well-differentiated pancreatic neuroendocrine tumors: from genetics to therapy. Nat Rev Gastroenterol Hepatol 9, 199–208 (2012). https://doi.org/10.1038/nrgastro.2012.9

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