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

Abstract

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. GEP-NENs were analyzed using next-generation sequencing (NGS; MiSeq on 47 genes, NextSeq on 592 genes), IHC, and <i>in situ</i> 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. In total, 724 GEP-NENs were examined: GI (<i>N</i> = 469), PNEN (<i>N</i> = 255), HG (<i>N</i> = 135), and LG (<i>N</i> = 335). Forty-nine percent were female, and median age was 59. Among LG tumors, the most frequently mutated genes were <i>ATRX</i> (13%), <i>ARID1A</i> (10%), and <i>MEN1</i> (10%). HG tumors showed <i>TP53</i> (51%), <i>KRAS</i> (30%), <i>APC</i> (27%), and <i>ARID1A</i> (23%). Immune-related biomarkers yielded a lower prevalence in LG tumors compared with HG [MSI-H 0% vs. 4% (<i>P</i> = 0.04), PD-L1 overexpression 1% vs. 6% (<i>P</i> = 0.03), TMB-high 1% vs. 7% (<i>P</i> = 0.05)]. Compared with LG, HG NENs showed a higher mutation rate in <i>BRAF</i> (5.4% vs. 0%, <i>P</i> < 0.0001), <i>KRAS</i> (29.4% vs. 2.6%, <i>P</i> < 0.0001), and <i>PI3KCA</i> (7% vs. 0.3%, <i>P</i> < 0.0001). When compared with GI, PNEN carried higher frequency of <i>MEN1</i> (25.9% vs. 0.0%, <i>P</i> < 0.0001), <i>FOXO3</i> (8.6% vs. 0.8%, <i>P</i> = 0.005), <i>ATRX</i> (20.6% vs. 2.0%, <i>P</i> = 0.007), and <i>TSC2</i> (6.3% vs. 0.0%, <i>P</i> = 0.007), but lower frequency of mutations in <i>APC</i> (1.0% vs. 13.8%, <i>P</i> < 0.0001). Significant molecular differences were observed in GEP-NENs by tumor location and grade, indicating differences in carcinogenic pathways and biology.