Abstract C119: Somatic and germline heterogeneity across colorectal cancer patient characteristics: Implications for early cancer detection
Authors: Srinivasan Preethi , Gutman Boris , Bristow Sara L. , Wu Hsin-Ta , Salari Raheleh , Swenerton Ryan , Kawli Trupti , Aleshin Alexey , Rabinowitz Matthew , Zimmermann Bernhard , Mitchell Breeana L. , Reiter Johannes G. 
Published: December 2023

Abstract
A deeper understanding of germline and somatic genomic landscapes across a broad population is critical to optimal performance of early cancer detection assays for all patients. Here, we investigated germline and somatic landscapes in patients with colorectal cancer (CRC). A total of 2,303 de-identified patients with stage I-IV CRC who had commercial, personalized, tumor-informed ctDNA testing (SignateraTM) ordered were included. Ancestry was inferred based on DNA extracted from blood samples using Principal Component Analysis and assigned to African (AFR), East Asian (EAS), European (EUR) and Southeast Asian (not included in ancestry-specific analyses because of sample size). Proportions of patients with somatic driver mutations and pathogenic germline variants (PGVs) in CRC-associated genes were calculated overall and across patient characteristics including age of disease onset (&lt;45 years: 15.8%, 45-65 years: 49.5%, &lt;65 years: 34.7%), sex (female, 47.3%), disease stage (I: 5.8%, II: 29.8%, III: 41.1%, IV: 18.0%), microsatellite stability vs instability (MSS: 83.8%, MSI: 16.2%). Among all patients, the most common somatic driver mutations were in APC (75.5%), TP53 (65.3%), TTN (48.6%), and KRAS (41.9%). PGVs were observed in 7.6% of patients (high-penetrance 4.3%, moderate-penetrance 0%, low-penetrance 2.7%, uncertain-penetrance 0.6%). Lynch syndrome (LS) genes were responsible for most high-penetrance findings (78.8%). PGV rates decreased with older age (&lt;45 years: 13.2%, 45-65 years: 8.1%, &gt;65 years: 5.1%) and was higher in patients with MSI (21.5%) compared to MSS (5.2%). PGV rates were similar regardless of patient sex (male, 8.2%; female, 7.5%) and CRC stage (I: 6.0%, II: 9.3%, III: 7.4%, IV: 8.0%). The genomic landscape of CRC was influenced by genetic ancestry. MSI rates were highest in EAS patients (20.6%, EUR: 16.4%, AFR: 9.9%). The most common somatic driver mutations were similar to the overall cohort: APC (AFR: 83.4%, EAS: 76.7%, EUR: 74.3%), TP53 (AFR: 68.4%, EAS: 70.4%, EUR: 64.2%), TTN (AFR: 47.8%, EAS: 48.4%, EUR: 48.9%) and KRAS (AFR: 51.4%, EAS: 35.0%, EUR: 41.2%). PGV rates were similar across ancestries (AFR: 8.3%, EAS: 7.6%, EUR: 7.6%), but high-penetrance genes were most common in EAS (6.7%) compared to AFR (5.5%) and EUR (3.7%) patients. LS genes were enriched in EAS patients compared to EUR patients (EAS 6.7%, EUR 2.8%, p&lt;0.005). 80% of patients with PGVs in LS genes underwent loss of heterozygosity in the tumor. Mutational signature 1 (aging) was the most common among all cancers, regardless of germling findings. Mutational signatures 6 (mismatch repair deficiency) and 18 (8-oxoguanine-associated mutagenesis) were enriched in patients with high-penetrance PGVs (i.e., LS genes) and low-penetrance PGVs (i.e., monoallelic MUTYH), respectively. These results demonstrate that integrated analysis of germline and somatic findings across various patient characteristics is critical for an optimal approach for developing risk stratification strategies pertaining to early cancer detection.
Citation Format: Preethi Srinivasan, Boris Gutman, Sara L. Bristow, Hsin-Ta Wu, Raheleh Salari, Ryan Swenerton, Trupti Kawli, Alexey Aleshin, Matthew Rabinowitz, Bernhard Zimmermann, Breeana L. Mitchell, Johannes G. Reiter. Somatic and germline heterogeneity across colorectal cancer patient characteristics: Implications for early cancer detection [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C119.