Abstract 1153: Large-scale genomic profiling of colorectal cancer
Authors: Vasily N. Aushev, Samuel Rivero-Hinojosa, Avinash Ramu, J. Bryce Ortiz, Adham Jurdi, Alyssa Antonopoulos, Alexey Aleshin, Axel Grothey
Journal: Cancer Research (2025)

Abstract Background: Colorectal cancer (CRC) is a heterogeneous disease driven by a multitude of genomic alterations that influence tumor progression and clinical outcomes. Genomic profiling plays a crucial role in identifying actionable mutations and understanding the molecular drivers of CRC. In this study, we analyzed genomic data from Natera’s proprietary Real-World Database, comprising more than 100, 000 CRC patients, to characterize the mutational landscape of the disease and investigate patterns across clinical and molecular subgroups. Methods: We performed an exploratory analysis of the whole-exome sequencing (WES) of tumor tissue data generated as part of commercial circulating tumor DNA testing (SignateraTM) in patients with CRC between May 2019 and November 2024. After excluding non-USA patients, clinical trial participants, and those with no informed consent or not passing QC for WES data, 73, 591 patients were included in the analysis. Variant calling was performed using Mutect2 and VarScan2 callers. MSI status was determined using the MSIsensor algorithm. For prevalence analysis, only non-synonymous mutations were included. Results: In this analysis of 73, 591 patients, the male/female ratio was 52.6%/47.1%, with cancer stages distributed as follows: stage I (11.4%), II (19.3%), III (26.7%), IV (21.7%), and other/unavailable (20.9%). The most frequently mutated genes were APC (65.6%), TP53 (57.3%), and KRAS (35.8%). The most common individual mutations were KRAS G12D (10.8%), ACVR2A K437X (9.9%), and BRAF V600E (8.4%). Microsatellite instability (MSI) was observed to be MSI-High in 11% of cases overall, with stagewise prevalence 11.2%/18.2%/10.8%/6.6% for stage I/II/III/IV, respectively. MSI status significantly influenced genomic landscape with MSI-high tumors exhibiting a significantly higher prevalence of ACVR2A K437X (72.7% vs 1.3%), BRAF V600E (45.1% vs 4.3%), and RNF43 G659X (42.8% vs 0.5%) compared to MSS tumors. Tumor location data were available for 50.9% of cases with a colon/rectal ratio of 72.3%/25.3%. Rectal tumors had a significantly lower prevalence of MSI-high status (2.3% vs 14.9%) and the associated mutations (ACVR2A K437X: 1.9% vs 12.8%, BRAF V600E: 1.5% vs 12.0%, RNF43 G659X: 0.65% vs 7.8%), but a higher prevalence of TP53 mutations (gene-level 71.3% vs 60.6%, variant-level R175H 7.1% vs 5.6%). When stratified by stage, BRAF V600E prevalence appeared lower in stage IV compared to stage I - III, however, this difference was not statistically significant after adjusting for MSI and tumor location. Conclusions: Our study represents one of the largest real-world genomic analyses in CRC, providing critical insights into the mutational landscape across clinical and molecular subgroups. These data enhance our understanding of the genomic drivers of CRC. Future studies will explore the associations between genomic subtypes, treatment patterns, and outcomes in this real-world patient population. Citation Format: Vasily N. Aushev, Samuel Rivero-Hinojosa, Avinash Ramu, J. Bryce Ortiz, Adham Jurdi, Alyssa Antonopoulos, Alexey Aleshin, Axel Grothey. Large-scale genomic profiling of colorectal cancer [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 1153.