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INTERNATIONAL CONGRESS OF

CancerGenetics

• Germline Polymorphisms in Chromatin Regulatory Genes Modulate Gut Microbiome and Colorectal Cancer Risk

• Narges Safari,^1,* Melika Motaheyar,² Zahra Dolati,³ Sogand Fallahfar,⁴ Soodeh Tavakoli,⁵
  1. Department of Veterinary Medicine, Garmsar Branch, Islamic Azad University, Garmsar, Iran.
  2. Faculty of Veterinary Medicine, University of Semnan, Semnan, Iran
  3. Department of Veterinary Medicine, Garmsar Branch, Islamic Azad University, Garmsar, Iran
  4. Department of Veterinary Medicine, Garmsar Branch, Islamic Azad University, Garmsar, Iran
  5. Independent Veterinarian, Tehran, Iran
  
  
  
• Introduction: Colorectal cancer (CRC) is the third most common cancer globally, underscoring the need to identify risk factors for effective prevention. Germline polymorphisms in chromatin regulatory genes, such as histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), regulate gene expression and immune responses, shaping gut microbiome composition [1, 2]. These interactions may drive carcinogenesis via microbiome-derived metabolites, like SCFAs, which modulate host epigenetics [3]. This study explores how these polymorphisms influence CRC risk and examines translatable insights from companion animals (dogs and cats) with similar tumour profiles [4].
• Methods: Multi-omics datasets (genomics, epigenomics, metatranscriptomics) from human cohorts (n=500, including 250 EO-CRC and 250 LO-CRC, mean ages 45 and 65 years) and companion animals (n=100, dogs and cats) were analysed. Machine learning with XAI (using SHAP tools) detected microbial signatures and mbQTLs. Statistical analyses included logistic regression for mbQTL associations and t-tests for microbial taxa abundance differences. Data were sourced from public repositories (e.g., TCGA) and collaborator cohorts. Statistical power (80%) was calculated using G*Power.
• Results: Germline polymorphisms in chromatin regulatory genes significantly altered gut microbiome composition. HDAC3 variants were linked to reduced microbial diversity (Shannon index, p<0.01) and increased pro-inflammatory taxa (Fusobacterium nucleatum, p<0.05), elevating CRC risk. DNMT1 variants correlated with higher anti-carcinogenic bacteria (Faecalibacterium prausnitzii, p<0.05), reducing risk. Butyrate, an SCFA, inhibited HDACs, increasing histone acetylation and modulating inflammation (IL-6, p<0.01) and proliferation (MYC, p<0.05) genes. EO-CRC exhibited distinct microbial signatures compared to LO-CRC (p<0.001), with stronger host-microbiome interactions in younger patients. Multi-omics and XAI identified predictive biomarkers for CRC progression (AUC=0.85). Similar genetic-microbiome patterns were observed in companion animals.
• Conclusion: Germline polymorphisms in chromatin regulatory genes modulate gut microbiome composition and CRC risk via epigenetic mechanisms. Multi-omics and machine learning approaches enable predictive biomarker discovery, paving the way for precision oncology and personalised prevention. Future clinical trials should test microbiome-targeted interventions in high-risk groups.
• Keywords: Gut microbiome Colorectal cancer (CRC) Germline polymorphisms, Microbiome-derived metabolites Pre