Abstract LB145: Identification of potent DIAPH3 variants as a powerful biomarker for targeting Native Hawaiian colorectal cancer population

Abstract Colorectal Cancer (CRC) is the second leading cause of cancer-related deaths in the U.S. population, but minority groups experience significant disparities. Native Hawaiians (NH), who make up 0.4% of the U.S. population, face a higher mortality rate compared to Whites, with a rate of 52 per 100,000 in males (vs. 44 per 100,000) and 37 per 100,000 in females (vs. 34 per 100,000). This elevated CRC death rate among both NH males (52 vs. 44) and females (37 vs. 34) compared to the non-NH population highlights CRC as a major health disparity in the NH community. This disparity underscores the need for effective cancer strategies to address both the disease and related inequities. In this study, we conducted DNA and RNA sequencing on tissue samples from Native Hawaiians, including 41 colorectal cancer (CRC) samples and 41 control samples, obtained from the University of Hawaii Cancer Center (UHCC) Biorepository. Our analysis revealed notably high mutation rates in the Diaphanous-Related Formins 3 (DIAPH3) gene. The mutation profile of DIAPH3 was distinct from that of other ethnic groups, prompting us to focus on identifying specific DIAPH3 variants that could be targeted for this population. Given the varied roles of DIAPH3 across different cancer types, we expanded our analysis to assess DIAPH3 expression in Pan-cancer datasets, cancer cell lines, and NH-CRC formalin-fixed paraffin-embedded (FFPE) tissue samples. These samples exhibited elevated DIAPH3 mRNA expression and protein levels. TNM (Tumor, Node, Metastasis) plots revealed higher DIAPH3 expression in tumor samples compared to controls. Although DIAPH3 survival curves for COAD and READ cancers showed elevated expression, the difference was not statistically significant, suggesting that DIAPH3 may act as a potential prognostic biomarker for Native Hawaiian CRC patients with high expression. Building on these observations, we investigated DIAPH3 expression in CRC cell lines by overexpressing full-length wild-type DIAPH3. Our results indicated that DIAPH3 functions as a tumor-promoting gene, as demonstrated by cell migration, wound healing assay, clonogenic and MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assays. In contrast, silencing DIAPH3 with siRNA suppressed CRC cell growth. We hypothesize that the loss of specific regions within the DIAPH3 coding sequence could influence the progression of CRC in the Native Hawaiian population. Based on these preliminary findings and the unique DIAPH3 mutation profile observed in Native Hawaiians, we plan to develop DIAPH3 variants that mirror these mutations for further characterization using in vitro functional assays. Ultimately, this research aims to improve our understanding of the disproportionately high CRC mortality rates among Native Hawaiians and inform the development of strategies to address these disparities. Specifically, the identification of potent DIAPH3 variants could provide valuable early detection biomarkers and serve as promising candidates for targeted NH-CRC therapies. Citation Format: Sudhir Kumar Rai, Isam Mohd-Ibrahim, Yuanyuan Fu, Asmita Pandey, Li Ma, Yu Chen, Yujia Qiu, Mayumi Jijiwa, Masaki Nasu, Hua Yang, Youping Deng. Identification of potent DIAPH3 variants as a powerful biomarker for targeting Native Hawaiian colorectal cancer population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB145.