O-8 Somatic and germline heterogeneity across colorectal cancer patient characteristics: Implications for early cancer detection

A deeper understanding of both germline and somatic genomic landscapes across a broad population is critical to ensuring optimal performance early cancer detection assays for all patients. Here, we investigated the mutational landscape in patients with colorectal (CRC). total 2,303 de-identified stage I-IV CRC who had commercial, personalized, tumor-informed ctDNA testing (SignateraTM) ordered were eligible study. Ancestry was inferred based on DNA extracted from blood samples using Principal Component Analysis single nucleotide polymorphisms assigned African (AFR), East Asian (EAS), European (EUR) Southeast (not included ancestry-specific analyses because sample size). Proportions driver mutations pathogenic variants (PGVs) CRC-associated genes calculated overall various patient characteristics including age disease onset (< 45 years: 15.8%, 45-65 49.5%, < 65 34.7%), sex (female, 47.3%), (I: 5.8%, II: 29.8%, III: 41.1%, IV: 18.0%), microsatellite stability vs instability (MSS: 83.8%, MSI: 16.2%). Among patients, most common APC (75.5%), TP53 (65.3%), TTN (48.6%), KRAS (41.9%). PGVs observed 7.6% (high-penetrance 4.3%, moderate-penetrance 0%, low-penetrance 2.7%, uncertain-penetrance 0.6%). Lynch syndrome (LS) responsible high-penetrance findings (78.8%). PGV rates decreased older ( 5.1%) higher MSI compared MSS (21.5% vs. 5.2%). similar regardless (male, 8.2%; female, 7.5%) 6.0%, 9.3%, 7.4%, 8.0%). Genetic ancestry associated differences CRC. highest EAS (20.6%), followed by EUR (16.4%) AFR (9.9%) The cohort: (AFR: 83.4%, EAS: 76.7%, EUR: 74.3%), 68.4%, 70.4%, 64.2%), 47.8%, 48.4%, 48.9%) 51.4%, 35.0%, 41.2%). ancestries 8.3%, 7.6%, 7.6%), but (6.7%) (5.5%) (3.7%) LS enriched (EAS 6.7%, 2.8%, p MUTYH), respectively. These results demonstrate that integrated analysis an approach developing risk stratification strategies pertaining detection.