Abstract 6150: MMP14 and MKLN1 as colorectal cancer susceptibility genes and a drug repurposing candidate from genome-wide association study in South Korea

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Abstract Background: One of the major topics about colorectal cancer (CRC) is to find susceptible genes. Furthermore, functional interpretation of post-GWAS analysis gains attention and various approaches to find drug-repurposing candidates are used in cancer research. Our study aims to identify susceptible genes for CRC and provide drug-repurposing candidates. Methods: CRC patients in Seoul National University Hospital with prospective follow-up were recruited. From blood-derived DNA, genome-wide SNPs were genotyped using the Korea Biobank Array and 409,063 SNPs were extracted. SNP-based logistic regression model was fit for the event of CRC estimating beta values. Furthermore, post-GWAS analysis was conducted using regulatory function, multiple annotation and gene expression database. Drug-repurposing candidate was identified through the pre-trained deep neural network with susceptible genes. Results: We used 500 participants of CRC cases and 1,500 participants of healthy controls. For GWAS, statistically significant associations were mapped to MKLN1, MMP14, PTPN14 and MKL2 genes. For post-GWAS analysis, strong associations were found for MKLN1 (rs75170436, 7q32.3, Beta=-0.90, P-value=5.90×10-13) and MMP14 (rs3751489, 14q11.2, Beta=-1.91, P-value=2.31×10-12). From the drug-repurposing analysis, PPARδ/β agonist (GW0742; Binding score=3.79(MKLN1), 12.06(MMP14)) was identified for both genes with the highest score. Conclusions: We revealed MKLN1 and MMP14 genes as susceptible genes associated with CRC development. Additionally, we identified PPARδ/β agonist (GW0742) as a drug-repurposing candidate for the treatment of CRC. These findings can promote the understanding of CRC development and provide a novel therapeutic candidate for CRC patients in the future. Citation Format: Dabin Yun, Jung-Ho Yang, Sun-Seong Kweon, Jin-ah Sim, Minjung Kim, Ji Won Park, Seung Yong Jeong, Aesun Shin, Nan Song. MMP14 and MKLN1 as colorectal cancer susceptibility genes and a drug repurposing candidate from genome-wide association study in South Korea [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6150.