The evolving (epi)genetic landscape of pancreatic neuroendocrine tumours

Abstract

Neuroendocrine neoplasms (NENs) are a relatively rare group of heterogeneous tumours originating from neuroendocrine cells found throughout the body. Pancreatic NENs (PanNENs) are the second most common pancreatic malignancy accounting for 1–3% of all neoplasms developing in the pancreas. Despite having a low background mutation rate, driver mutations in MEN1, DAXX/ATRX and mTOR pathway genes (PTEN, TSC1/2) are implicated in disease development and progression. Their increased incidence coupled with advances in sequencing technologies has reignited the interest in PanNEN research and has accelerated the acquisition of molecular data. Studies utilising such technological advances have further enriched our knowledge of PanNENs’ biology through novel findings, including higher-than-expected presence of germline mutations in 17% of sporadic tumours of no familial background, identification of novel mutational signatures and complex chromosomal rearrangements and a dysregulated epigenetic machinery. Integrated genomic studies have progressed the field by identifying the synergistic action between different molecular mechanisms, while holding the promise for deciphering disease heterogeneity. Although our understanding is far from being complete, these novel findings have provided the optimism of shaping the future of PanNEN research, ultimately leading to an era of precision medicine for NETs. Here, we recapitulate the existing knowledge on pancreatic neuroendocrine tumours (PanNETs) and discuss how recent, novel findings have furthered our understanding of these complex tumours.

Mutational landscape and potential therapeutic targets for sporadic pancreatic neuroendocrine tumors based on target next‑generation sequencing

“…signaling pathway genes, including phosphatase and tensin homolog (PTEN), TSC complex subunit 1, TSC complex subunit 2, DEP domain containing 5, GATOR1 subcomplex subunit and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), were previously identified to be commonly mutated in PNETs (8,10). Additional novel germline mutations in the DNA repair genes, mutY DNA glycosylase, checkpoint kinase 2 and BRCA2 DNA repair-associated (BRCA2), and recurrent inactivating mutations or chromosomal rearrangements in chromatin-remodeling genes, including SET domain containing 2, histone lysine methyltransferase (SETD2), AT-rich interaction domain 1A (ARID1A) and lysine methyltransferase 2C (KMT2C), have also been reported (4).…”

Pancreatic neuroendocrine tumors: Therapeutic challenges and research limitations

“…Recently, cross-species analysis of mice and human panNET tissues illustrate the existence of three molecular subtypes of PNETs including Islet/Insulinoma tumors [IT (less aggressive, and express genes associated with differentiated mature β-cells)]; metastasis-like/primary [MLP (invasive and express genes associated with immature β-cells, and stem cells)], and intermediate (express genes similar to IT and are moderately invasive)[ 18 ]. Next-Gen sequencing illustrates that commonly mutated genes associated with neoplasia pathogenesis are not significantly implicated in PNET development and progression[ 19 ]. However, hyperactivation of PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways have been well documented to be the main regulators of proliferation in NETs[ 20 ].…”

Molecular profile of pancreatic neuroendocrine neoplasms (PanNENs): Opportunities for personalized therapies

“…It has been demonstrated that increasing numbers of molecular pathways are involved in the biology and clinical behavior of panNENs (Table 1). 6,12‐15 A 2003 study by Maitra et al 16 in well differentiated panNETs identified approximately 200 differentially expressed genes. The results of the International Cancer Genome Consortium effort on panNENs identified 4 pathways: DNA damage repair, chromatin remodeling, telomere alteration, and PI3K/mTOR signaling 17 …”