Molecular Genetics of Pancreatic Endocrine Tumours


Pancreatic tumours with neuroendocrine phenotype comprise 1–2% of all pancreatic tumours and commonly occur in a sporadic setting. Up to 10% of pancreatic neuroendocrine tumours (PNETs) may occur as part of inherited tumour‐predisposing syndromes, including multiple endocrine neoplasia type 1, von Hippel–Lindau disease, neurofibromatosis type 1, tuberous sclerosis complex and glucagon cell adenomatosis. Recent advances in genetics and pathology have allowed better understanding of the role of genetic abnormalities that underlie hereditary and sporadic PNETs. Ongoing research in this fast‐changing field has led to the discovery of mutations in key genes that determine how tumours begin, evolve and behave. Major specific tumour pathways of PNETs involve abnormalities of MEN1, DAXX/ATRX, and mammalian target of rapamycin (mTOR) pathway genes (PTEN, TSC2, and PIK3CA). New knowledge in the field of genetics of PNETs potentially permits development of effective diagnostic methods and targeted therapies aimed at improving prognosis and disease‐free survival rates.

Key Concepts

  • Hereditary and sporadic pancreatic neuroendocrine tumours (PNETs) demonstrate characteristic histo‐morphology and genetics that determine biology, treatment response and prognosis.
  • Tumour‐predisposing syndromes with increased risk of developing PNETs include multiple endocrine neoplasia type 1 (MEN1), von Hippel–Lindau disease (VHL), neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC).
  • Recent advances in the pathology and genetics of PNETs have unraveled the role of genetic abnormalities in tumour pathways that may lead to better diagnostic and therapeutic paradigms.
  • Major specific tumour pathways of PNETs involve abnormalities of MEN1, DAXX/ATRX, and mammalian target of rapamycin (mTOR) pathway genes (PTEN, TSC2, and PIK3CA).

Keywords: pancreas; endocrine neoplasms; genes; hereditary syndromes; sporadic neoplasms; functional tumours

Figure 1. Illustration demonstrating the molecular pathogenesis of pancreatic neuroendocrine tumours.


Agarwal SK, Kennedy PA, Scacheri PC, et al. (2005) Menin molecular interactions: insights into normal functions and tumourigenesis. Hormone and Metabolic Research 37 (6): 369–374. PubMed PMID: 16001329.

Balogh K, Racz K, Patocs A and Hunyady L (2006) Menin and its interacting proteins: elucidation of menin function. Trends in Endocrinology and Metabolism 17 (9): 357–364. PubMed PMID: 16997566.

Capurso G, Festa S, Valente R, et al. (2012) Molecular pathology and genetics of pancreatic endocrine tumours. Journal of Molecular Endocrinology 49 (1): R37–R50. PubMed PMID: 22586144.

Cassol C and Mete O (2015) Endocrine manifestations of von Hippel‐Lindau disease. Archives of Pathology & Laboratory Medicine 139 (2): 263–268. PubMed PMID: 25611110.

Corcos O, Couvelard A, Giraud S, et al. (2008) Endocrine pancreatic tumours in von Hippel‐Lindau disease: clinical, histological, and genetic features. Pancreas 37 (1): 85–93. PubMed PMID: 18580449.

Curatolo P, Bombardieri R and Jozwiak S (2008) Tuberous sclerosis. Lancet 372 (9639): 657–668. PubMed PMID: 18722871.

Dogeas E, Karagkounis G, Heaphy CM, et al. (2014) Alternative lengthening of telomeres predicts site of origin in neuroendocrine tumour liver metastases. Journal of the American College of Surgeons 218 (4): 628–635. PubMed PMID: 24655849. Pubmed Central PMCID: 4332797.

Duerr EM and Chung DC (2007) Molecular genetics of neuroendocrine tumours. Best Practice & Research Clinical Endocrinology & Metabolism 21 (1): 1–14. PubMed PMID: 17382262.

Ehehalt F, Franke E, Pilarsky C and Grutzmann R (2010) Molecular pathogenesis of pancreatic neuroendocrine tumours. Cancer 2 (4): 1901–1910. PubMed PMID: 24281208. Pubmed Central PMCID: 3840460.

Halfdanarson TR, Rubin J, Farnell MB, Grant CS and Petersen GM (2008) Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumours. Endocrine‐Related Cancer 15 (2): 409–427. PubMed PMID: 18508996. Pubmed Central PMCID: 2693313.

Hammel PR, Vilgrain V, Terris B, et al. (2000) Pancreatic involvement in von Hippel‐Lindau disease. The Groupe Francophone d'Etude de la Maladie de von Hippel‐Lindau. Gastroenterology 119 (4): 1087–1095. PubMed PMID: 11040195.

Ishida E, Yamada M, Horiguchi K, et al. (2011) Attenuated expression of menin and p27 (Kip1) in an aggressive case of multiple endocrine neoplasia type 1 (MEN1) associated with an atypical prolactinoma and a malignant pancreatic endocrine tumour. Endocrine Journal 58 (4): 287–296. PubMed PMID: 21441703.

Jansson L and Carlsson PO (2002) Graft vascular function after transplantation of pancreatic islets. Diabetologia 45 (6): 749–763. PubMed PMID: 12107718.

Jensen RT, Berna MJ, Bingham DB and Norton JA (2008) Inherited pancreatic endocrine tumour syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer 113 (7 Suppl): 1807–1843. PubMed PMID: 18798544. Pubmed Central PMCID: 2574000.

Jiao Y, Shi C, Edil BH, et al. (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumours. Science 331 (6021): 1199–1203. PubMed PMID: 21252315. Pubmed Central PMCID: 3144496.

Knudson AG (1996) Hereditary cancer: two hits revisited. Journal of Cancer Research and Clinical Oncology 122 (3): 135–140. PubMed PMID: 8601560.

Loffler KA, Mould AW, Waring PM, Hayward NK and Kay GF (2012) Menin and p53 have non‐synergistic effects on tumourigenesis in mice. BMC Cancer 12: 252. PubMed PMID: 22708734. Pubmed Central PMCID: 3433377.

Lott ST, Chandler DS, Curley SA, et al. (2002) High frequency loss of heterozygosity in von Hippel‐Lindau (VHL)‐associated and sporadic pancreatic islet cell tumours: evidence for a stepwise mechanism for malignant conversion in VHL tumourigenesis. Cancer Research 62 (7): 1952–1955. PubMed PMID: 11929809.

McKenna LR and Edil BH (2014) Update on pancreatic neuroendocrine tumours. Gland Surgery 3 (4): 258–275. PubMed PMID: 25493258. Pubmed Central PMCID: 4244504.

Milne TA, Hughes CM, Lloyd R, et al. (2005) Menin and MLL cooperatively regulate expression of cyclin‐dependent kinase inhibitors. Proceedings of the National Academy of Sciences of the United States of America 102 (3): 749–754. PubMed PMID: 15640349. Pubmed Central PMCID: 545577.

Missiaglia E, Dalai I, Barbi S, et al. (2010) Pancreatic endocrine tumours: expression profiling evidences a role for AKT‐mTOR pathway. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 28 (2): 245–255. PubMed PMID: 19917848. Pubmed Central PMCID: 4288616.

Nikolova G, Jabs N, Konstantinova I, et al. (2006) The vascular basement membrane: a niche for insulin gene expression and Beta cell proliferation. Developmental Cell 10 (3): 397–405. PubMed PMID: 16516842.

Norton JA, Krampitz G and Jensen RT (2015) Multiple endocrine neoplasia: genetics and clinical management. Surgical Oncology Clinics of North America 24 (4): 795–832. PubMed PMID: 26363542. Pubmed Central PMCID: 4571281.

Oberg K (2010) Pancreatic endocrine tumours. Seminars in Oncology 37 (6): 594–618. PubMed PMID: 21167379.

Ro C, Chai W, Yu VE and Yu R (2013) Pancreatic neuroendocrine tumours: biology, diagnosis, and treatment. Chinese Journal of Cancer 32 (6): 312–324. PubMed PMID: 23237225. Pubmed Central PMCID: 3845620.

Shi C and Klimstra DS (2014) Pancreatic neuroendocrine tumors: pathologic and molecular characteristics. Seminars in Diagnostic Pathology 31 (6): 498–511. PubMed PMID: 25441311.

Vortmeyer AO, Huang S, Lubensky I and Zhuang Z (2004) Non‐islet origin of pancreatic islet cell tumours. The Journal of Clinical Endocrinology and Metabolism 89 (4): 1934–1938. PubMed PMID: 15070966.

Wang Y, Ozawa A, Zaman S, et al. (2011) The tumour suppressor protein menin inhibits AKT activation by regulating its cellular localization. Cancer Research 71 (2): 371–382. PubMed PMID: 21127195. Pubmed Central PMCID: 3076053.

Wiedenmann B, Pavel M and Kos‐Kudla B (2011) From targets to treatments: a review of molecular targets in pancreatic neuroendocrine tumours. Neuroendocrinology 94 (3): 177–190. PubMed PMID: 21893937.

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 tumours. Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 25 (7): 1033–1039. PubMed PMID: 22575867. Pubmed Central PMCID: 3547622.

Zhang J, Francois R, Iyer R, et al. (2013) Current understanding of the molecular biology of pancreatic neuroendocrine tumours. Journal of the National Cancer Institute 105 (14): 1005–1017. PubMed PMID: 23840053.

Further Reading

Verbeke CS (2010) Endocrine tumours of the pancreas. Histopathology 56: 669–682. DOI: 10.1111/j.1365-2559.2010.03490.x.

Zhou C, Zhang J, Zheng Y and Zhu Z (2012) Pancreatic neuroendocrine tumours: a comprehensive review. International Journal of Cancer 131: 1013–1022. DOI: 10.1002/ijc.27543.

Zikusoka MN, Kidd M, Eick G, Latich I and Modlin IM (2005) The molecular genetics of gastroenteropancreatic neuroendocrine tumours. Cancer 104: 2292–2309. DOI: 10.1002/cncr.21451.

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Katabathina, Venkata S, Wilcoxson, Robert (Dan), and Prasad, Srinivasa R(May 2016) Molecular Genetics of Pancreatic Endocrine Tumours. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024992]