Comprehensive Genomic Profiling of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs).

Purpose: GEP-NENs are rare malignancies with increasing incidence. Their molecular characteristics are still undefined. We explored the underlying biology of GEP-NENs and the differences between gastrointestinal (GI) and pancreatic (PNEN), high-grade (HG), and low-grade (LG) tumors.

Experimental Design: GEP-NENs were analyzed using next-generation sequencing (NGS; MiSeq on 47 genes, NextSeq on 592 genes), IHC, and hybridization. Tumor mutational burden (TMB) was calculated on the basis of somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci.

Results: In total, 724 GEP-NENs were examined: GI ( = 469), PNEN ( = 255), HG ( = 135), and LG ( = 335). Forty-nine percent were female, and median age was 59. Among LG tumors, the most frequently mutated genes were (13%), (10%), and (10%). HG tumors showed (51%), (30%), (27%), and (23%). Immune-related biomarkers yielded a lower prevalence in LG tumors compared with HG [MSI-H 0% vs. 4% ( = 0.04), PD-L1 overexpression 1% vs. 6% ( = 0.03), TMB-high 1% vs. 7% ( = 0.05)]. Compared with LG, HG NENs showed a higher mutation rate in (5.4% vs. 0%, < 0.0001), (29.4% vs. 2.6%, < 0.0001), and (7% vs. 0.3%, < 0.0001). When compared with GI, PNEN carried higher frequency of (25.9% vs. 0.0%, < 0.0001), (8.6% vs. 0.8%, = 0.005), (20.6% vs. 2.0%, = 0.007), and (6.3% vs. 0.0%, = 0.007), but lower frequency of mutations in (1.0% vs. 13.8%, < 0.0001).

Conclusions: Significant molecular differences were observed in GEP-NENs by tumor location and grade, indicating differences in carcinogenic pathways and biology.