Abstract 3854: Revealing mismatch repair deficiency in Egyptian colorectal cancer patients using next generation sequencing a predictive biomarker for immunotherapy efficacy
Authors: Youssef Amira Salah El-Din , Ragab Mohamed , Ateya Heba Aly , Elberry Mostafa , Fathy Nasra , Elleithy Asmaa , Zekri Abdel Rahman , Ahmed Ola Sayed , Nassar Auhood 
Published: March 2024

Abstract
Background: The mismatch repair (MMR) deficiency is a potential predictive biomarker for immunotherapy efficacy, particularly in colorectal cancer (CRC), where alterations in various DNA polymerases and MMR genes are prevalent. The accumulation of these genetic aberrations may cause a subsequent neoantigen formation. study aimed to identify the mutational profile of DNA polymerases and MMR genes in Egyptian CRC patients', providing insights into colorectal carcinogenesis and potential implications for immunotherapy.
Material and Methods: Thirty-nine blood samples from Egyptian patients with CRC and twenty-four blood samples from healthy controls were collected. The libraries were prepared by Qiaseq UMI-based targeted panel and sequenced via an Ion proton sequencer. The detected genetic variants with an average coverage of 500x were annotated against Cosmic, dbSNP, and ClinVar databases using Ingenuity Variant analysis (IVA).
Results: Our results revealed that the POLD1andPOLE genes (DNA polymerases) in the CRC patients, when compared with healthy controls, harbored 10 and 13 pathogenic variants (PVs), respectively. These PVs cause a loss of their functionality. The most frequently detected PVs and likely to be novel in the POLD1gene werec.44delC(31%)andc.3008delG(31%), while c.3510delA(18%)andc.2793delT(15%) were detected in the POLE gene. As per MMR genes, our study showed that the MLH1, MLH3, MSH2, MSH3, MSH6, PMS1,and PMS2 harbored 8, 13, 23, 19, 22, 23, and 7 PVs, respectively. The highly frequent PV in the MLH1wasc.469delT (26%), while the novel most frequently detected PV in the MLH3 wasc.1467delA (23%). Moreover, the PVs found highly frequent are c.2647delA (36%) in MSH2,c.1148delA (41%)in the MSH3, and c.2079delA (44%) in the MSH6. RegardingPMS1/2, the most frequently detected PV and likely to be novel was c.1647delA (44%) in PMS1, while c.869delT (13%) was the most prevalent PV in PMS2.
Conclusion: Our results revealed the MMR mechanism deficiency in Egyptian CRC patients offering crucial insights into colorectal carcinogenesis and neoantigen formation. These insights are pivotal for developing ethnic-based personalized immunotherapy strategies in Egyptian CRC patients, shedding light on their role in CRC. Interestingly, we have identified novel variants in the DNA repair enzymes. However, further investigations and validations are required to corroborate these findings and explore their clinical significance in the personalized medicine.
Citation Format: Amira Salah El-Din Youssef, Mohamed Ragab, Heba Aly Ateya, Mostafa Elberry, Nasra Fathy, Asmaa Elleithy, Abdel Rahman Zekri, Ola Sayed Ahmed, Auhood Nassar. Revealing mismatch repair deficiency in Egyptian colorectal cancer patients using next generation sequencing a predictive biomarker for immunotherapy efficacy [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 3854.