DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas (PanNECs) and pancreatic neuroendocrine tumors (PanNETs)

Abstract

Pancreatic Neuroendocrine Neoplasms (PanNENs) comprise a rare and heterogeneous group of tumors derived from neuroendocrine cells of the pancreas. Despite recent genetic and epigenetic characterization, biomarkers for improved patient stratification and personalized therapy are sparse and targeted therapies, including the mTOR inhibitor Everolimus, have shown limited success. To better define PanNENs tumors we performed multi-omic analyses on 59 tumors with varying grades (NET G1, NET G2, NET G3 and NEC), combining mutational profiling with epigenetic analysis and targeted proteomics. An unsupervised approach using DNA methylation profiles uncovered two major subgroups in PanNENs resembling α-like and β-like cells. DNA copy number analysis further divided the α-like subgroup into two distinct groups, indicating differential mechanisms of tumorigenesis from α-cells. β-like tumors however showed two distinct groups at the epigenetic level and suggest NET G3/NEC samples are of β-cell origin.DNA mutation profiling clearly separated α and β-cell derived PanNENs, whereby only αlike tumors had mutations within MEN1/DAXX/ATRX tumor suppressor genes. Targeted proteomic analysis further indicated overexpression of distinct components of the mTOR pathway. Our data provide further insights into the potential mechanisms behind PanNEN heterogeneity and form a basis for future diagnostic and therapy relevant patient stratification.

Transcriptomic Deconvolution of Neuroendocrine Neoplasms Predicts Clinically Relevant Characteristics

“…Technically, the latter two were aggregated into a single artificial cell type called 'exocrine-like' by summation over the acinar and ductal proportions. The reasons for designing a mixed endocrine/exocrine model were: (i) the trans-differentiation of endocrine to exocrine cell types and vice versa occurs in mouse models of pancreatic injury, regeneration, and carcinogenesis [49][50][51], (ii) panNEC share mutational profiles with pancreatic adenocarcinoma [52][53][54] and may exhibit areas of pancreatic adenocarcinoma [12], (iii) the DNA methylation analyses in panNEC suggested acinar cells as the cell of origin [55], and (iv) adult pancreatic stem or progenitor-like cells are proposed to reside in the exocrine compartment [56][57][58][59]. Three panNEN and five GEP-NEN datasets were deconvolved with twelve combinations of the deconvolution algorithm and scRNA training dataset to uncover whether a transcriptomic deconvolution of panNENs and non-pancreatic GEP-NENs was possible and to identify which combination was most effective.…”

Role of Endoscopic Ultrasound in the Diagnosis of Pancreatic Neuroendocrine Neoplasms

“…Young et al performed a comprehensive analysis of the immune response and showed that immunotherapy may be clinically beneficial for patients with the metastasislike primary (MLP)-1 subtype [ 106 ]. In addition, Simon et al performed multi-omics on PNENs of various grades and revealed the mechanisms involved in PNENs [ 107 ]. If PNENs can be further genetically analyzed and subdivided into Ki-67 grading before surgery, it will become an attractive option for the management and preoperative risk stratification of patients with PNENs.…”