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Abstract
Neuroendocrine tumors (NETs) of the small intestine undergo large chromosomal and methylation changes. The objective of this study was to identify methylation differences in NETs and consider how the differentially methylated genes may impact patient survival. Genome-wide methylation and chromosomal copy number variation (CNV) of NETs from the small intestine and appendix were measured. Tumors were divided into three molecular subtypes according to CNV results: chromosome 18 loss (18LOH), Multiple CNV, and No CNV. Comparison of 18LOH tumors with MultiCNV and NoCNV tumors identified 901 differentially methylated genes. Genes from the G-protein coupled receptor (GPCR) pathways are statistically overrepresented in the differentially methylated genes. One of the highlighted genes from the GPCR pathway is somatostatin (SST), a clinical target for NETs. Patient survival based on low versus high methylation in all samples identified four significant genes (p < 0.05) OR2S2, SMILR, RNU6-653P, and AC010543.1. Within the 18LOH molecular subtype tumors, survival differences were identified in high versus low methylation of 24 genes. The most significant is TRHR (p < 0.01), a GPCR with multiple FDA-approved drugs. By separating NETs into different molecular subtypes based on chromosomal changes, we find that multiple GPCRs and their ligands appear to be regulated through methylation and correlated with survival. These results suggest opportunities for better treatment strategies for NETs based on molecular features.
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1 University of Utah, Huntsman Cancer Institute, Salt Lake City, USA (GRID:grid.223827.e) (ISNI:0000 0001 2193 0096); University of Utah School of Medicine, Department of Biomedical Informatics, Salt Lake City, USA (GRID:grid.223827.e) (ISNI:0000 0001 2193 0096)
2 University of Utah, Huntsman Cancer Institute, Salt Lake City, USA (GRID:grid.223827.e) (ISNI:0000 0001 2193 0096); University of Utah, Department of Pathology, Salt Lake City, USA (GRID:grid.223827.e) (ISNI:0000 0001 2193 0096)
3 University of Utah, Huntsman Cancer Institute, Salt Lake City, USA (GRID:grid.223827.e) (ISNI:0000 0001 2193 0096)
4 University of Utah, Huntsman Cancer Institute, Salt Lake City, USA (GRID:grid.223827.e) (ISNI:0000 0001 2193 0096); University of Utah, Division of Epidemiology, Department of Internal Medicine, Salt Lake City, USA (GRID:grid.223827.e) (ISNI:0000 0001 2193 0096)
5 University of Utah School of Medicine, Division of General Surgery, Department of Surgery, Salt Lake City, USA (GRID:grid.223827.e) (ISNI:0000 0001 2193 0096)
6 Intermountain Healthcare, Medical Oncology, Salt Lake City, USA (GRID:grid.420884.2) (ISNI:0000 0004 0460 774X)