Abstract 6463: Highly frequent gene mutations and co-occurring genes analysis in colorectal cancer

Abstract

Abstract Background: Colorectal cancer (CRC) is the second most leading cause of cancer-related deaths worldwide. Understanding the molecular alterations that drive CRC is critical for improving patient outcomes. Next-generation sequencing (NGS) has revolutionized CRC molecular profiling by simultaneous analysis of multiple genes with high accuracy and sensitivity. In this study, we analyzed a cohort of CRC formalin-fixed paraffin-embedded (FFPE) samples to identify highly frequent gene mutations and co-occurring genes in CRC. Methods: FFPE samples from CRC patients tested from January 2020 to May 2023 were analyzed using NeoTYPE® Colorectal Tumor Profile. This profile analyzes 44 biomarkers through a combination of NGS focusing on a panel of 36 genes known to be frequently mutated in CRC, as well as 3 FISH and 3 IHC biomarkers. Gene mutation frequency, co-occurring mutation genes and clinical significance were explored and analyzed. In addition, immunotherapy markers, Microsatellite Instability (MSI) and Tumor Mutation Burden (TMB) were assessed. Results: A total of 2,920 patients (1,577 men and 1,343 women) with CRC were included in this study. Average sequence coverage was 2386X with mean minor allelic frequency of 30%. A higher average number of variant allele frequency were observed in metastatic versus primary colorectal cancer (P < .001). We found that APC, TP53, KRAS, PIK3CA and ARID1A were the most frequently mutated genes. APC truncated mutation p. R1450* were the most common mutations. KRAS, PIK3CA and TP53 missense mutations are the prevalent consequence. Notably, a subset of patients exhibited high microsatellite instability (MSI-H) or TMB high, indicating potential eligibility for immune checkpoint inhibitor therapy. In addition, we found APC mutations co-occurring with TP53 or KRAS mutations (p <.001) in our cohort. Conclusion: Our results provide insight into the genetic landscape of CRC and highlight the importance of understanding co-occurring mutations in this disease. Specifically, APC mutations frequently coincide with TP53 mutations, jointly contributing to the onset of CRC. TP53 often play a role in promoting genomic instability and evading mechanisms that regulate cell growth. The identification of highly frequent mutations and co-occurring genes may have important implications for the development of targeted therapies and personalized treatment approaches for CRC patients. Citation Format: Qinqin Zha, Frank Scarpa, Madhu Rengaraj, Anna Juncker-Jensen. Highly frequent gene mutations and co-occurring genes analysis in colorectal cancer [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 6463.