Abstract 4958: Mutational disparities in colorectal cancers of White Americans, Alabama African Americans, and Oklahoma American Indians revealed ANGEL2 as an African American CRC proneness candidate gene

Abstract Introduction: The high incidence and mortality rates of colorectal cancer (CRC) in Alabama African Americans (AAs) and Oklahoma American Indians (AIs) are recognized as cancer disparities, yet the underlying causes have been poorly demonstrated. Our previous study of transcriptomic profiles of CRCs of Alabama AAs, Oklahoma AIs, and white people from both states revealed molecular disparities and differentially expressed genes (DEGs) in the racial groups. Methods/Procedures: By evaluating CRC whole-exome sequencing and mutational profiles, we report sets of mutated genes whose frequencies differed significantly (p<0.05) in a race-specific manner. Secondary screening with a CRC database (cBioportal database for bowel cancer) showed 42, 38, and 35 “survival-critical genes (SCGs)” (i.e., genes whose mutations/alterations are associated with significant differences in the patients’ survival rates) among the differentially mutated genes, suggesting that the mutations have a functional impact on cancer. Notable SCGs with race-pronounced variants were different from DEGs and their involved pathways included nucleotide catabolism (GDA, NT5M, XDH) and cell cycle checkpoints (CLIP1, PSMB2, PSMD3, TP53) for AAs, and extracellular matrix organization (COL4A4, LAMA1, LAMA2, NRXN1) for AIs (Benjamini-Hochberg adjusted p<0.05). Most of the SCGs with race-pronounced variants (35 SCGs out of 42 in whites, 29 of 38 AAs, and 30 of 35 AI) are under-investigated with less than ten CRC-related publications in PubMed. New results: We considered multitudes of factors to select gene(s) for further validation, such as (i) statistical significance, (ii) being a SCG, (iii) type of variant/mutation (variants occurring in open reading frame may be prioritized with an assumption of direct effects on the protein function, compared with likely indirect effects of intron variants), (iv) amount and quality of existing work, and (v) available resources, then proceeded to validate the SCGs with race-pronounced variants. Among the candidate genes, ANGEL2 with Alabama African American-pronounced variant is involved in 3'-UTR-mediated mRNA stabilization and negative regulation of mitotic cell cycle. ANGEL2 expression increases in rat colon tumor (IHC) and in human CRCs in TCGA (vs normal; <0.0001), implicating a role in regulating CRC development. Prospective: Cancer-influencing genes with minority race-pronounced variants have evaded discovery by being diluted in all-inclusive tumor data analysis. The inclusion of these SCGs with race-pronounced variants in the clinical CRC next-generation sequencing panels and the development of targeting drugs will serve as refinements for precision medicine to overcome racial disparities in health outcomes of CRC. Citation Format: Hiroshi Y. Yamada, Madhusmita Rout, Chao Xu, Gary Sanghera, Surya Singh, Venkateshwar Madka, Farrukh Afaq, Katherine T. Morris, Dharambir K. Sanghera, Upender Manne, Chinthalapally V. Rao. Mutational disparities in colorectal cancers of White Americans, Alabama African Americans, and Oklahoma American Indians revealed ANGEL2 as an African American CRC proneness candidate gene [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 4958.