Abstract PO-131: Therapeutic molecular targets in Egyptian colorectal cancer patients: Time for ethnic personalized medicine

Abstract

Abstract Background: Colorectal cancer (CRC) in Egypt is one of the most prevalent and deadly tumor. The pathogenesis of CRC is complex and affected by multiple factors: genetic, epigenetic and familial history of polyposis and long standing inflammatory condition. Aim: This study aimed to sequence custom panel consists of 96 tumor suppressor genes and oncogenes frequently associated with colorectal cancer (CRC) to identify the potential molecular therapeutic targets and their frequencies in the Egyptian CRC patients which may help in developing personalized therapy. Material and methods: Biopsy samples were collected from 62 CRC Egyptian patients. The libraries were performed using Qiaseq UMI-based targeted panel and sequenced via Ion proton sequencer. The detected genetic variants with an average coverage of 500x were annotated against Cosmic and dbSNP and Clinvar databases. Further Variant and Pathway analysis were performed using both Ingenuity Variant analysis (IVA) and Ingenuity Pathway analysis (IPA). Results: The Pathway Analysis revealed that Wnt-B-catenin, P53 signaling, RTK-RAS, TGF-beta signaling pathways were the most altered pathways in the CRC patients (73%. 72%, 38% & 36%, respectively). Regarding P53 signaling pathway, it has been shown that TP53 variant (c.215C>G (44%)) was the most frequent single nucleotide polymorphism (SNP) and drug response variant involved in drug efflux resistance mechanism, this variant was found to be more related to the Europe, Jewish and Latino populations (0.73, 0.72 & 0.71, respectively). In RTK-RAS signaling pathway, we identified many variants that are associated with resistant mechanism to anti EGFR therapy as well as drug efflux resistance mechanism; RET (c.2071G>A (37%)) & KIT (c.1621A>C (13%)) SNPs were the most frequently detected variants among the studied groups while KRAS (c.35G>T(8%) & c.38G>A(3%)), ERBB2(c.922G>A(2%) & c.2690G>A(2%)), NRAS (c.35G>T(2%)) and BRAF(c.1781A>G(2%) & c.1799T>A(3%)) were less frequent variants. Moreover, we identified many variants as molecular targets for PD-1 and PDL-1 immunotherapy; 8 variants in APC (c.3754delT (65%), c.1742delA (13%), c.1495C>T (2%), c.2055G>A (2%), c.2309C>G (2%), c.4588G>T (2%), c.8446C>T (2%) &c.3856G>T (2%)), three in SMAD4 (c.1064A>G (2%), c.1081C>T (3%) & c.1088G>A (2%)), two in PIK3CA (c.1173A>G (16%) & c.3140A>G (2%)) and one in PIK3R1 (c.978G>A (23%)). The two variants PIK3CA (c.1173A>G) & PIK3R1 (c.978G>A)) were found to be more related to the African ethnicity (0.21 & 0.38, respectively). Conclusion: In this data set, we shed the light on the most frequently identified molecular therapeutic targets and the most altered pathways that are crucial for understanding cancer predisposition and developing ethnic-based personalized therapies in the Egyptian CRC patients. Citation Format: Amira Salah El-Din Youssef, Auhood Nassar, Mai M. Lotfy, Mohamed A. Abdel-Fattaf, Abdel-Rahman N. Zekri. Therapeutic molecular targets in Egyptian colorectal cancer patients: Time for ethnic personalized medicine [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-131.