Rabindra Roy’s research while affiliated with Georgetown University Medical Center and other places

Objective The Long-Evans Cinnamon (LEC) rat is a model for Wilson’s disease (WD) and is associated with chronic inflammation and hepatocellular carcinoma. This study performed a gene expression microarray using total RNA extracted from LEC liver tissue at 84 weeks late chronic hepatitis, tumor-adjacent normal (84 weeks N), and 84 weeks tumor (84 weeks T). Understanding the difference between a tumor and adjacent normal within the same animal can be very intriguing as both are in the same environment, and one becomes and sustains a tumor status, but the other still maintains its normalcy. Experiment Total RNA was extracted from liver tissue of three LEC rats at 84 weeks N and 84 weeks T and hybridized to the Affymetrix GeneChip Rat Genome 230 2.0 Array (Affymetrix Inc, Santa Clara). GeneGO Pathways software was used to analyze the differentially expressed genes using a cutoff of P-value ≤0.05 and FDR <0.25% and a fold change +/- 2. A volcano plot was generated to visualize significant gene change expression between 84 weeks N vs 84 weeks T. Agglomerative Hierarchical and K-means clustering were used to group similarly expressed genes into clusters and build a hierarchy of clusters. Each cluster obtained from K-means clustering analysis within the up or down-regulated groups were checked for pathway analysis to understand the interplay between biological pathways by QIAGEN Ingenuity® Pathway Analysis (QIAGEN IPA). In addition − log(p) > 1.3, a z-score cut-off͕ ≥ 2 for activation and a z-score cutoff ≤ -2 for inhibition was used to call a pathway activation, and inhibition is significant. Result The seven most significant pathways that were activated are the S100 Family Signaling Pathway, Extracellular Matrix Organization, Response to Elevated platelet cytosolic Ca2+, HMGB1 Signaling, Sertoli Cell-Sertoli Cell Junction Signaling, Cachexia Sunaina Pathway, and Nicotine Degradation II. Except for Nicotine Degradation II pathway, all other pathways are shown activated in non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) patients previously but shown in the WD model for the first itme. The Nicotine Degradation II pathway is shown to be activated in the NAFLD patient before. Conclusion To our knowledge, this is the first report where gene expression analysis was done between tumor-adjacent normal and tumor within the same animal in the WD model. Our results identified multiple pathways in the model that could lead us to new diagnostics and therapeutic targets when validated. Citation Format Ritam Adhikari, Chiranjeev Dash, Rabindra Roy. Unveiling dichotomies between liver cancer and adjacent normal tissues in Wilson’s disease model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2348.

Simple Summary Non-Hispanic Black breast cancer survivors have poorer outcomes than White survivors, but the biological mechanisms underlying these disparities are unclear. We discovered novel race-based differences in systemic DNA damage and repair activity among breast cancer survivors. This finding suggests DNA damage and repair are important basic science mechanisms in cancer disparities. Abstract Non-Hispanic Black breast cancer survivors have poorer outcomes and higher mortality rates than White survivors, but systemic biological mechanisms underlying these disparities are unclear. We used circulating leukocytes as a surrogate for measuring systemic mechanisms, which might be different from processes in the target tissue (e.g., breast). We investigated race-based differences in DNA damage and repair, using a novel CometChip assay, in circulating leukocytes from breast cancer survivors who had completed primary cancer therapy and were cancer free. We observed novel race-based differences in systemic DNA damage and repair activity in cancer survivors, but not in cells from healthy volunteers. Basal DNA damage in leukocytes was higher in White survivors, but Black survivors showed a much higher induction after bleomycin treatment. Double-strand break repair activity was also significantly different between the races, with cells from White survivors showing more sustained repair activity compared to Black leukocytes. These results suggest that cancer and cancer therapy might have long-lasting effects on systemic DNA damage and repair mechanisms that differ in White survivors and Black survivors. Findings from our preliminary study in non-cancer cells (circulating leukocytes) suggest systemic effects beyond the target site, with implications for accelerated aging-related cancer survivorship disparities.