Site-Specific Genomic Alterations in a Well-Differentiated Pancreatic Neuroendocrine Tumor With High-Grade Progression

Abstract

The major categories of pancreatic neuroendocrine tumor (PanNET) are well-differentiated NET and poorly differentiated neuroendocrine carcinoma. Sequencing of these tumors has identified multiple important genes in the pathogenesis of PanNETs, such as DAXX/ATRX, MEN1, TP53, RB, and mTOR pathway genes. We identified a case of well-differentiated PanNET with high-grade progression with simultaneous low- and high-grade histologic regions containing variable genomic profiles. We performed tumor microdissection and analyzed both regions using a 409-gene comprehensive cancer panel using next-generation sequencing in addition to immunohistochemical and morphologic studies. The low-grade region showed a change in the DAXX gene as a copy number variant (CNV) deletion. The high-grade region showed CNV deletion changes in the DAXX gene as well as the MEN1 gene. We observed additional mutational changes in the PTEN gene and SMAD4 gene in the high-grade region. Our data support that high-grade progression in PanNETs may be the result of the progressive accumulation of genetic changes (CNVs and point mutational changes) within the body of the tumor. Next generation sequencing may provide pathologists and clinicians with ancillary information to accurately characterize and treat these tumors.

Differences between Well-Differentiated Neuroendocrine Tumors and Ductal Adenocarcinomas of the Pancreas Assessed by Multi-Omics Profiling

“…PNETs are relatively uncommon neoplasms, constituting 1-5% of pancreatic tumors [9,23,24]. Two major categories of PNETs are well-differentiated NETs and poorly-differentiated neuroendocrine carcinomas (NECs) [25].…”

EPB41L5 is Associated With the Metastatic Potential of Low-grade Pancreatic Neuroendocrine Tumors

“…Furthermore, a PNET tissue biomarker that is able to distinguish LG-PNETs at risk of metastasis from those that are not would enormously benefit appropriate management of this disease. Research has focused on distinguishing GAs that drive the biological behavior of PNETs from those that drive PECAs (18)(19)(20)(21)(22)(23). GAs in genes involved in chromatin remodeling, such as MEN1, DAXX, and ATRX, as well as those in phosphatase and tensin homolog (PTEN) loss, have been found to be enriched in G1, G2, and G3 PNETs, whereas PECAs have been determined to be enriched in GAs that lead to the inactivation of TP53 and/or RB1 and to EMT (5, 19,20,[24][25][26][27][28][29].…”

Mechanisms of Resistance in Gastroenteropancreatic Neuroendocrine Tumors

“…Tang LH et al reported 31 well-differentiated PanNETs with a morphologically apparent high-grade component, and did not reveal additional mutations, including TP53 mutations, in the high-grade component [ 46 ]. However, Martin, et al analyzed a PanNET with focal high-grade progression and found an increased CNV and additional mutations in PTEN and SMAD4 only in the high-grade component, suggesting that genetic heterogeneity is seen in rare PanNETs [ 47 ]. Consistent with this study, we have also observed that rare PanNETs with a focal high-grade component can have TP53 mutations in addition to gene mutations commonly present in well-differentiated NETs.…”