DNA methylation regulates TREM1 expression to modulate immune responses and drive progression in colorectal neuroendocrine neoplasm as a potential therapeutic target.

BACKGROUND: Colorectal neuroendocrine neoplasms (CrNENs) are rare malignancies with limited therapeutic options and poorly understood molecular mechanisms. The roles of genetic, epigenetic, and immune factors in CrNEN progression remain largely unknown. METHODS: We employed an integrative multi-omics approach combining two-sample Mendelian randomization, Bayesian colocalization, methylation quantitative trait loci (mQTLs), cis-expression QTLs (cis-eQTLs), protein QTLs (pQTLs), summary data-based Mendelian randomization, mediation analyses, immunohistochemistry validation, and pan-cancer validation using TCGA and GTEx data, including DNA methylation profiling using the SMART, UALCAN, UCSC Xena and MethSurv platforms to provide integrative insights into potential epigenetic regulation in oncogenesis. Molecular docking was performed to identify candidate therapeutic compounds that targeted the genes. RESULTS: Our analyses identified TREM1 as a robust therapeutic candidate, with elevated TREM1 expression promoting the progression of CrNEN. Epigenetic analysis revealed that hypomethylation at the cg04451353 locus was associated with increased TREM1 expression, mediating approximately 74% of the CrNEN risk attributable to this epigenetic mechanism. Immune mediation analysis suggested that increased TREM1 expression may influence the infiltration of specific immune subsets (CD14 + CD16- monocytes, CD25 + + CD8br Tregs, CD3 on Tregs, CD3 on CD39 + secreting Tregs, CD3 on CD8br Tregs, and CD28 on CD39 + CD8br Tregs), with each subset contributing approximately 1-4% to the total 16.65% increase in CrNEN risk. Pan-cancer validation underscored the oncogenic potential and prognostic significance of TREM1 across various malignancies, with particular relevance in the colorectal cancer. Molecular docking analysis suggested favorable binding affinities between TREM1 and bioactive natural compounds, such as artemisinin and quercetin, which may support their potential as therapeutic candidates. CONCLUSIONS: Multi-omics analysis suggests that TREM1 may play a role in CrNEN pathogenesis, with potential implications as a therapeutic target. Further validation and research are needed to confirm its clinical relevance and therapeutic potential.