Comprehensive genomic profiling of high grade neuroendocrine gastrointestinal neoplasms

Background. Gastro-entero-pancreatic (GEP) high-grade neuroendocrine neoplasms (H-NENs) are a heterogenous group of aggressive neoplasms which includes neuroendocrine tumours (NETs) G3 and neuroendocrine carcinomas (NECs). Due to the rarity of these neoplasms, a comprehensive molecular characterization is still lacking. Aim of the study. The aim of this study is to define the genomic profile of H-NENs (NET G3, NEC <55% ki-67 and NEC ≥55% ki-67). Material and methods. Genomic characterization of 40 cases of GEP-H-NENs (20 cases of NET G3, 8 of NEC <55% ki-67 and 12 of NEC ≥55% ki-67) was subject to DNA and RNA assay targeting 523 genes by Next Generation sequencing, assessing of all variant types including microsatellite instability (MSI) and Tumour Mutational Burden (TMB) (TrueSight Oncology 500, Illumina). Results. Based on genomic data, our samples were classified as MSI, chromosomally instable (CIN) and genomically stable (GS). MSI was found in 1/20 (5%) NET G3, 0/8 NEC <55% ki-67 and 2/12 (16%) NEC ≥55% ki-67. CIN was found in 6/20 (30%) NET G3, 5/8 (63%) NEC<55% ki-67 and 6/12 (50%) NEC ≥55% ki-67. 13/20 (65%) NET G3, 3/8 (38%) NEC <55% ki-67 and 4/12 (33%) NEC ≥55% ki-67 were GS. A high TMB was found in 0/20 NET G3, 1/8 (13%) NEC <55% ki-67 and 5/12 (42%) NEC ≥55% ki-67. The most commonly found amplifications comprise: CDK4/6, EGFR, FGF10, RICTOR, MYC family genes, MET. Fusions genes were found in 6/40 (15%) cases and included: HFM1-ETV1, SEL1L-EGFR, CNTN5-KMT2A, KMT2A-EED, BCL2-KCTD, FLT1-HUWE1, SLC37A1-ERG. Conclusions. This study sheds light on the biology of H-NENs. Genomic profiling of H-NENs has shown that NET G3, NEC <55% ki-67 and NEC ≥55% ki-67 have are a heterogenous in their molecular profiles, while sharing share some frequently altered genes. Further genomic analysis are required to identify potential druggable alterations and predictive biomarkers.