Abstract 2399: Genomic and transcriptomic profiling of advanced early-onset colorectal cancer

Abstract Background: Incidence rates of early-onset colorectal cancer (EO-CRC) are increasing in high-income countries, yet the underlying causes and optimal clinical management strategies remain unclear. Methods: Comprehensive molecular profiling was conducted on colorectal cancer patients enrolled in the DKTK MASTER program, which includes patients with fresh tumor material, age <50 years, and/or rare cancer types. Profiling utilized RNA sequencing (RNA-seq) and whole-exome (WES) or whole-genome sequencing (WGS). WES data was analyzed for genomic variants, tumor mutational burden (TMB), and mutational signatures. WGS underwent metagenomic analysis, mapping unmapped reads to a metagenome assembled genomes (MAGs) of German CRC patients to identify CRC-associated microbiome. Transcriptomic data were analyzed for consensus molecular subtypes (CMS) and inflammation signatures. A small cohort of late-onset CRC patients (>50 years, n=10) and TCGA-COAD data were used as reference cohorts. Results: The cohort included 168 patients, 154 aged <50 years (median age: 43; range: 19-50) and 10 aged >50 years (4 age data unavailable). Primary tumors were located in the right colon (n=32) or left colon (n=127) (9 NA). Common molecular alterations included TP53 (77%), APC (70%), and KRAS (48%) mutations. The median TMB was 3.5 mutations/megabase and was comparable to TCGA-COAD (3.8 mutations/megabase). TMB>10 Mut/Mb was only identified in 2 samples. Age was not associated with inflammation levels. CMS subtypes I-IV were identified in 15%, 26%, 9%, and 34% of cases, resembling TCGA-COAD but with slightly higher CMS IV and lower CMS III. Findings suggest a molecular profile similar to late-onset CRC (LO-CRC). Mutational signatures in WES analysis revealed a prevalence of clock-like and defective DNA damage repair signatures (SBS1, SBS3, SBS5, SBS6). Clock-like signatures (SBS1, SBS5) showed no significant age-related differences. Metagenomic analysis revealed distinct prevalence patterns and notable dissimilarity in gut-associated microbes between early- and late-onset cohorts. Significant differences in abundance were observed in Firmicutes such as Blautia wexlerae, Coprococcus comes, Veillonella parvula, and Bacteroidetes such as Prevotella copri. Conclusion: Comprehensive molecular profiling revealed no significant differences between sporadic EO-CRC and LO-CRC, thus not suggesting different clinical management in this setting. The identification of distinct microbiome compositions warrants further investigation. Citation Format: Erika Zuljan, Shuba Varshini Alampalli, Eric Blanc, Bruno Köhler, Rene-Filip Jackstadt, Ulrich Keller, Sebastian Stintzing, Ulrich Keilholz, Hanno Glimm, Stefan Fröhling, Dieter Beule, Ivan Jelas, Damian Rieke, Manuela Benary. Genomic and transcriptomic profiling of advanced early-onset 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 2399.