Abstract 5669: Rare germline variants on SI gene and the possibility of colorectal cancer development

Abstract Research on cancer and germline variants has been ongoing. The germline variant in CPGs has been linked to cancer development. BRCA 1/2 is a typical case and oncometabolite production due to germline variants of the FH gene can affect the cancer progression. Among the genes related to IEMs, SI (Sucrase-isomaltase) is an enzyme that converts sucrose into glucose and fructose to allow normal metabolism in the small intestine. In addition, SI is highly specifically expressed in the gastrointestinal tract (nTPM = 435.9). So, we focused on and hypothesized the biological traits of the SI gene and alteration caused by germline variants could affect colorectal cancer progression. We used the public cancer databases PCAWG and TCGA and the healthy cohorts 1000G. We confirmed carriers with SI germline variants are the top gene with a high prevalence of IEM-related genes. We also established the hypothesis the SI gene may match “Knudson’s Two-hit hypothesis”. Depending on whether germline variants in IEM-related genes or not, we performed regression and utilized LOH (Loss of heterozygosity) information for each cancer sample from the public database. In COAD and STAD which are in the gastrointestinal tract, SI was confirmed to have a high tendency for LOH according to germline prevalence. Next, we performed DEG analysis and found SI germline carriers had upregulated genes related to the IFIT (Interferon-induced proteins with tetratricopeptide repeats) family. STRING network analysis also showed significance in pathways associated with “Interferon alpha/beta signaling (FDR = 0.00058)”, “Antiviral defense (FDR = 0.0016)”, “Innate immunity (FDR = 0.0317)”, and “Tetratricopeptide repeats (FDR = 0.0413)”. The following GSEA revealed that “KEGG_CYTOSOLIC DNA-SENSING PATHWAY” and “HALLMARK_INTERFERON_ALPHA_RESPONSE” were enriched in the SI germline carriers. In summary, it can be suggested immune regulation caused by SI germline variants may lead to cancer progression. We executed a follow-up analysis using the genes with low expression levels to the SI germline carriers. Among the down-regulated genes in the DEG, REG4 (Regenerating Family Member 4) and RELMβ (Resistin-Like Molecule Beta) genes were confirmed to express and function specifically only in the gastrointestinal tract. RELMβ is essential for preserving energy balance and glucose metabolism. As a validation at the protein level, we conducted IHC (Immunohistochemistry) on tissues from Korean colorectal cancer patients and confirmed lower REG4 and RELMβ expression were associated with poor prognosis. Our results suggest that SI germline carriers may cause colorectal cancer by affecting the immune system due to decreased SI enzyme function. Additionally, the decreased REG4 and RELMβ expression levels are associated with the SI germline variant and may affect cancer progression. Further analyses and experimental validations are still required. Citation Format: Seokhyeon Kim, Jeong Mo Bae, Youngil Koh, Sung-Soo Yoon. Rare germline variants on SI gene and the possibility of colorectal cancer development [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 5669.