Abstract 2289: Comprehensive multiomic analysis reveals different subtypes in neuroendocrine tumors from multiple origins
Authors: Puche Carlos Carretero , Soldevilla Beatriz , Gil Beatriz , La Salvia Anna , Lens-Pardo Alberto , Espinosa Paula , Anton-Pascual Beatriz , Gómez-López Gonzalo , Al-Shahrour Fátima , García-Carbonero Rocío 
Published: June 2022

Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors with a wide anatomical distribution and different clinical behaviors that share common “neuro” and “endocrine” properties. They are classified in well differentiated G1, G2 and G3 neuroendocrine tumors (NETs), or poorly differentiated neuroendocrine carcinomas (NECs) which are all G3. Some studies have assessed the NET molecular landscape of certain primary sites, but no cross-sites molecular assessment has been performed to date. Thus, we aimed to perform a comprehensive transcriptomic and methylomic characterization of large series of NENs of different anatomical origins in order to identify molecular subgroups, unravel genes and/or pathways involved, and explore their potential clinical relevance.
Transcriptomic and methylation data were obtained from tumor samples of 181 and 99 patients with NENs (37.02%G1; 54.7%G2 and 8.29%G3) using Clariom S Human microarrays and EPIC methylation arrays, respectively. Most common primary tumor site was the lung (43.1%), followed by the small intestine (35.4%), large intestine (8.8%), stomach (4.4%), pancreas (1.7%), other localizations (3.9%), and unknown primary (2.8%). Tumors were clustered using transcriptomic and methylation data by NMF and hierarchical clustering algorithms respectively, and differential expression (limma analysis) and gene set enrichment analysis (GSEA) was applied to transcriptomic data clusters
NENs were classified into three different clusters. Two of them (C1 and C3) showed an inverse transcriptomic profile, while C2 presented a mixed profile. We identified that C3 had the highest expression levels of neuroendocrine-related genes (somatostatin receptor SSTR5 LFC: 0.77 ; FDR: 1.52x10e-25 ; serotonin receptor HTR1A LFC: 0.79 ; FDR: 1.20X10e-20 ; VIP LFC: 0.64 ; FDR= 1.41x10e-10 etc), in lung primary tumor samples (50%) and methylation cluster 1 (82.14%). On the other hand, C1 was enriched in some important cancer-related pathways ( MYC targets NES -6.37 FDR &lt; 10-3; MTORC1 NES -3.78 FDR &lt; 10-3) and oxidative phosphorylation (NES -4.87 FDR &lt; 10-3) ; and showed a higher proportion of small intestine primary tumors (46.34%), Grade 2 tumors (73.17%) and methylation cluster 2 (75%).
NENs of different primary sites can be stratified into two major transcriptomic clusters, with a third cluster having a mixed expression profile. The groups with extreme transcriptomic signatures were enriched in neuroendocrine-related genes or principal cancer pathways. These results suggest a dedifferentiation from a more indolent neuroendocrine phenotype to more aggressive proliferative tumor types that could be driven partially with the methylation profile.
Citation Format: Carlos Carretero Puche, Beatriz Soldevilla, Beatriz Gil, Anna La Salvia, Alberto Lens-Pardo, Paula Espinosa, Beatriz Anton-Pascual, Gonzalo Gómez-López, Fátima Al-Shahrour, Rocío García-Carbonero. Comprehensive multiomic analysis reveals different subtypes in neuroendocrine tumors from multiple origins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2289.