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An integrative multi-omics strategy was used to connect genetic and epigenetic variation with immune regulation, including Mendelian randomization, Bayesian colocalization, mQTL/eQTL/pQTL analyses, mediation testing, and immunohistochemistry validation using TCGA and GTEx. Results highlight TREM1 as a robust candidate where cg04451353 hypomethylation elevates TREM1 and mediates most epigenetic risk, while TREM1 shapes specific immune infiltration patterns and shows therapeutic binding to natural compounds.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/dna-methylation-regulates-trem1-expression-to-modulate-immune-responses-and-drive-progression-in-colorectal-neuroendocrine-neoplasm-as-a-potential-therapeutic-target/376361/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/dna-methylation-regulates-trem1-expression-to-modulate-immune-responses-and-drive-progression-in-colorectal-neuroendocrine-neoplasm-as-a-potential-therapeutic-target/376361.png","ImageObject",300,407,{"name":92,"@type":93},"Fans","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-27","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":81},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the main therapeutic target identified in the study?","Question",{"text":112,"@type":113},"TREM1 is identified as a robust therapeutic candidate, with elevated TREM1 expression promoting colorectal neuroendocrine neoplasm progression.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does DNA methylation influence TREM1 in colorectal neuroendocrine neoplasms?",{"text":117,"@type":113},"Hypomethylation at the cg04451353 locus is associated with increased TREM1 expression and mediates approximately 74% of the colorectal neuroendocrine neoplasm risk attributable to this epigenetic mechanism.",{"name":119,"@type":110,"acceptedAnswer":120},"What immune-related mechanisms are linked to increased TREM1 expression?",{"text":121,"@type":113},"Mediation analysis indicates increased TREM1 expression may alter infiltration of specific immune subsets, with subsets contributing to an overall increased risk proportion reported in the results.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},376361,1790249081,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":81,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},5909892330395,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Guo et al. Discover Oncology (2025) 16:1624 [https://doi.org/10.1007/s12672-025-03468-1](https://doi.org/10.1007/s12672-025-03468-1)  \nDiscover Oncology  \nRESEARCH Open Access  \nDNA methylation regulates TREM1 expression  to modulate immune responses and drive progression in colorectal neuroendocrine neoplasm as a potential therapeutic target  \nHuimin Guo 1,2, Guiwen Zheng 1,2, Jia Li3, ShuzhanYao2, Qiang Jia 1, Jian Tan 1 and Zhaowei Meng 1,4*  \n*Correspondence:  \nZhaowei Meng [jamesmencius@163.com](jamesmencius@163.com)[ ](jamesmencius@163.com)1Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China 2Department of Nuclear Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China 3Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China 4Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin Medical University General Hospital, Tianjin 300052, China  \nAbstract  \nBackground 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.  \nMethods 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.  \n© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly","cbCaibiTZG6mnGbk","https://ap.wps.com/l/cbCaibiTZG6mnGbk","pdf",5096776,31,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusions\n# 1 Background","[{\"question\":\"What is the main therapeutic target identified in the study?\",\"answer\":\"TREM1 is identified as a robust therapeutic candidate, with elevated TREM1 expression promoting colorectal neuroendocrine neoplasm progression.\"},{\"question\":\"How does DNA methylation influence TREM1 in colorectal neuroendocrine neoplasms?\",\"answer\":\"Hypomethylation at the cg04451353 locus is associated with increased TREM1 expression and mediates approximately 74% of the colorectal neuroendocrine neoplasm risk attributable to this epigenetic mechanism.\"},{\"question\":\"What immune-related mechanisms are linked to increased TREM1 expression?\",\"answer\":\"Mediation analysis indicates increased TREM1 expression may alter infiltration of specific immune subsets, with subsets contributing to an overall increased risk proportion reported in the results.\"}]","DNA methylation regulates TREM1 expression to modulate immune responses and drive progression in colorectal neuroendocrine neoplasm as a potential therapeutic target | PDF",1790218374,78]