Abstract Background: African ancestry (AA) is associated with worse colorectal adenocarcinoma (COAD) outcomes compared to European Ancestry (EA), but the role that molecular drivers play in these differences remain imcompletely understood. Prior transcriptomic studies have reported immune-related differentially expressed genes between AA and EA tumors, but most did not not control for mismatch repair defficiency/ microsatellite instability-high (MMR-d/MSI-High) status or consider Consensus Molecular Subtype (CMS) classifications. MMR-d/MSI-High is a know modifier of tumor immune gene expression and is a clinical predictor of response to immunotherapy. We hypothesized that the transcriptioinal immune activation associated with MMR-d/MSI-High (ie CXCL10 expression) is attenuated in AA tumors compared to EA tumors. Methods: To disentangle the effects of ancestry and MMR status, we analyzed TCGA-COAD RNA-seq data (n = 348) and a validation cohort of FFPE samples (n = 118) from three U.S medical centers enriched for MMR-d/MSI-High tumors. TCGA samples' MMR status was classified using MANTIS scores. CMS subtypers were assigned using published machine learning-based classifiers (random forest). Multivariable linear models assessed ancestry by MMR interactions. Validation was performed on an independent set of FFPE COAD tumors enriched for MMR-d/MSI-high cases using RT-qPCR of CXCL10 relative to two reference genes (C!ORF43 and RAB7A). Expression of CD45 and CD3D was used to assess immune infiltration. Results: CXCL10 levels were higher in MMR-d vs MMR-p tumors (p0.0001), and lower in AA vs EA tumors ((p0.0001) in TCGA. However, the increase in CXCL10 associated with MMR-d status was attenuated in AA tumors. Among MMR-d tumors, EA cases showed a strong increase in CXCL10 expression (log2FC+1.84), whil AA cases showed a smaller increase (+0.59). Importantly 59% of EA MMR-d tumors were classified as CMS1, where as 0% of AA MMR-d tumors were assigned as CMS1. Instead, most AA MMR-d tumors were unclassified. In the independent FFP cohort, CXCL19 was significantly elevated in MMR-d/MSI-High tumors overall (p-0.01, but differences between AA and EA were not statistically significant. CXCL10 expression correlated stronly with CD45 and CD3D expression (correlation coefficent 0.05, p 0.0001), which is consistent with its role in immune infiltration. Conclusion: The immune activation typically observed in MMRd tumors is dimished in AA patients, potentially due to reduced representation in CMS1. This ancestry specific difference in transcriptional response to MMR-deficiency may contribute to differences in immunotherapy efficacy and highlights the limitations of CMS classifiers developed in predominantly EA cohorts. These findings emphasizes the need for ancestry-informed molecular classifiers and immune biomarkers in colorectal cancer. Citation Format: Dimitri F. Joseph, Seidu Adams, Alexandra Guillaume, Olorunseun Ogunwobi. Opposing effects of African ancestry and mismatch-repair enzyme deficiency/microsatellite instability-high in colorectal adenocarcinoma abstract. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A035.
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