Differential methylation of G-protein coupled receptor signaling genes in gastrointestinal neuroendocrine tumors

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.

SFXN3 is Associated with Poor Clinical Outcomes and Sensitivity to the Hypomethylating Therapy in Non-M3 Acute Myeloid Leukemia Patients

“…These findings indicated that the regulation of SFXN3 in tumors is multifaceted. DNA hypermethylation occurs in multiple genes, some of which are associated with G-protein-coupled receptors, appear in many cancers, and affect the efficiency of chemotherapy drugs [ 40 , 41 ]. Some tumor suppressor genes are affected by hypermethylation and promote tumor genesis and invasion through the ERK signaling pathway [ 42 ].…”

The Molecular Biology of Midgut Neuroendocrine Neoplasms

“…The receptor of this protein, somatostatin receptor (SSTR) 2 is the target of an Food and Drug Administration-approved theranostic. This study also identified multiple differentially methylated genes, which correlated with survival outcomes within the chromosome 18 LOH subgroup, including TRHR , another gene within the G-protein coupled receptor pathway that is the target of several Food and Drug Administration-approved therapies ( 30 ).…”

“…Further work in this area has identified differentially methylated genes that are evident between the 3 molecular subgroups. When comparing tumors with chromosome 18 LOH with the other 2 groups, 901 genes were found to be differentially methylated with a particular enrichment for genes from the G-protein coupled receptor pathway ( 30 ). These differentially methylated genes could give insight into potential therapeutic pathways, demonstrated by the differential methylation of the somatostatin ( SST ) gene.…”

DNA Methylation-Specific Analysis of G Protein-Coupled Receptor-Related Genes in Pan-Cancer

“…They found GPCRs were overrepresented among coding genes with elevated expression in solid tumors and GPCRs may be used as a biomarker for cancer [ 10 ]. Many studies have shown extensive methylation of GPCR in cancer, such as differential methylation of G protein-coupled receptor signaling genes in gastrointestinal neuroendocrine tumors [ 11 ].…”