Molecular Pathology of Pancreatic Endocrine Tumors

  • Gianfranco Delle Fave
  • Elettra Merola
  • Gabriele Capurso
  • Stefano Festa
  • Matteo Piciucchi
  • Roberto Valente
Reference work entry

Abstract

The molecular biology of pancreatic neuroendocrine tumors (pNETs) carcinogenesis is poorly understood and is generally different from that of exocrine pancreatic neoplasms. pNETs represent a rare group of neoplasms with heterogeneous clinicopathological features. They are generally sporadic but can also arise within very rare hereditary syndromes, such as multiple endocrine neoplasia type I (MEN-I), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). In these syndromes although a specific genotype/phenotype association with pNETs has been described, exact mechanisms leading to tumors development are still debated. Some clinical and biological features of pNETs associated with hereditary syndromes are similar in sporadic cases.

The presence of germline mutations has been indeed recently proved also in a high proportion of sporadic pNETs (17%) by whole genoming sequencing. These mutations include (beyond the well-known MEN1 and VHL) also other genes (such as BRCA2, or other of the mTOR pathway). Overall, main genomic changes involve gain of 17q, 7q, 20q, 9p, 7p, 9q and loss of 11q, 6q, 11p, 3p, 1p, 10q, 1q that identify the region of putative candidate oncogenes or tumor suppressor genes (TSGs) respectively. For some of them a possible relevant prognostic role has been described. “Classical” oncogenes involved in exocrine neoplasms (k-Ras, c-Jun, c-Fos) are of limited relevance in pNETs; on the contrary, overexpression of Src-like kinases and cyclin DI oncogene (CCNDI) has been described. As for TSGs, p53, DPC4/Smad, and Rb are not implicated in pNETs tumorigenesis, while for p16INK4a, TIMP-3, RASSF1A, and hMLH1 more data are available, with data suggesting a role for methylation as silencing mechanism. Different molecular pathways and the role of tyrosine kinase receptors have also been investigated in pNETs (EGF, c-KIT) with interesting findings especially for VEGF and m-TOR, which encourage clinical development. Microarray analysis of expression profiles has recently been employed to investigate pNETs, with a number of different strategies, even if these studies suffer from a number of limitations, mainly related with the poor repeatability and the poor concordance between different studies. However, apart from methodological limits, molecular biology studies are needed to better know this group of neoplasms, aiming at identifying novel markers and targets for therapy also highlighting relations with clinical outcome. Besides biomarkers recent studies are currently focusing on the role of the immune system in tumor pathogenesis of pNETs, paving the way to a new therapeutic approach also in these rare tumors: the immunotherapy.

Keywords

Pancreatic neuroendocrine tumors Carcinogenesis Germline-mutations Oncosuppressor genes mTOR 

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Gianfranco Delle Fave
    • 1
  • Elettra Merola
    • 2
  • Gabriele Capurso
    • 1
  • Stefano Festa
    • 1
  • Matteo Piciucchi
    • 1
  • Roberto Valente
    • 1
  1. 1.Digestive and Liver Disease Unit, II Medical School“Sapienza,” University of Rome, S. Andrea HospitalRomeItaly
  2. 2.Universitätsklinikum ErlangenErlangenGermany

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