Abstract 1196: Race-specific genetic and immunologic insights into colorectal cancer among Hawaiians

Abstract Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the US, and Native Hawaiians (NH) experience disproportionately higher colorectal cancer incidence and mortality in Hawaii and US. Race-specific genetic and immunologic factors may contribute to these disparities and their association with clinical outcomes. Methods: Tissue samples from NH and other race/ethnic patients diagnosed with primary CRC were obtained from the Hawaii Tumor Registry. RNA and DNA were extracted from tumor and adjacent normal tissues for RNA sequencing and whole genome sequencing. Differentially expressed genes (DEGs) for each cohort were identified via DESeq2 with q-value<0.05 and a cutoff of 2-fold change. From the RNA-seq gene expression profiles, we applied the ESTIMATE algorithm to calculate the overall immune cell infiltration score for each sample. And then, based on CIBERSORT to estimate the abundance of 22 immune cell types, we profiled the tumor-infiltrating immune cells present in the paired samples, respectively. Mutect2 from GATK, a variant caller, were used to detect possible somatic mutations including nonsynonymous SNVs and short insertions/deletions in the tumor genome. For driver gene discovery, the tool MutSig2CV were used, and significantly mutated genes (SMG) were identified by taking mutations of all samples as input and comparing them against background mutation rate. Results: In total, 2096 DEGs were identified between NH-CRC tumor and adjacent normal tissues, with 1740 transcripts and 80 mutations unique to NH compared to Caucasian cohort. To verify the “new highly mutated genes” identified in NH-CRC, we subsequently conducted the DNA-seq on tumor and matched adjacent normal tissues from NH-CRC patients and identified 36 significantly mutated genes in the NH-CRC cohort. Immune profiling revealed significant differences in immune cell infiltration between Native Hawaiians and Caucasians. In the Native Hawaiian cohort, the overall immune infiltration score was significantly lower in tumor tissues than adjacent normal tissues (P < 0.05). Specifically, NH-CRC tumors showed significantly higher fractions of activated dendritic cells, resting NK cells, and follicular helper T cells, while activated NK cells and plasma cells were significantly lower in tumor tissues compared to adjacent normal tissues (P < 0.05). Compared to Whites, NH-CRC tumors exhibited upregulation of activated dendritic cells and follicular helper T cells, and downregulation of activated NK cells. Conclusion: The identification of race-specific genetic signatures and distinctive tumor microenvironment characteristics offer new insights into CRC development and progression, underscoring the importance of population-specific biomedical research to improve patient outcomes. Citation Format: Yuanyuan Fu, Isam Mohd-Ibrahim, Mayumi Jijiwa, Masaki Nasu, Yu Chen, Hua Yang, Zhanwei Wang, Christina Wai, Brenda Hernandez, Youping Deng. Race-specific genetic and immunologic insights into colorectal cancer among Hawaiians [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 1196.