Abstract 6696: Genomic alterations associated with early-onset and late-onset colorectal cancer
Authors: Lander Eric M. , Rivero-Hinojosa Samuel , Aushev Vasily N. , Izaguirre-Carbonell Jesús , Jurdi Adham , Liu Minetta C. , Eng Cathy 
Published: April 2023

Abstract
Background: The causes of the rising incidence of early-onset colorectal cancer (EOCRC), defined as CRC in patients aged &lt;50, remain unknown. In this study, we evaluated tumor genomic differences in patients with EOCRC versus late-onset CRC (LOCRC, age &gt;60).
Methods: The international cohort included 13,262 patients diagnosed with stages I-III colon or rectal cancer who had ctDNA testing using a personalized and tumor-informed multiplex PCR assay (Signatera™ 16-plex bespoke mPCR NGS assay), from which whole-exome sequencing (WES) on the surgically resected tumor was performed. Tumor mutational burden (TMB) and microsatellite instability (MSI) status were derived from WES analysis. The prevalence of gene-wide mutations, pathogenic gene variants, and mutations in known oncogenic pathways was compared between EOCRC and LOCRC groups, stratified by TMB and MSI status. Fisher’s exact test was used to test significance between the groups and p-values were adjusted using the FDR method for multiple test correction.
Results: A total of 3,093 patients with EOCRC (70.8% colon, 27.4% rectal, 1.9% unknown) and 10,169 patients with LOCRC (79.9% colon, 18.3% rectal, 1.7% unknown) were included, where 9.0%/37.3%/53.7% were AJCC stages I, II, and III, respectively. Early-onset patients compared to late-onset patients had fewer cases of stage II CRC (30.7% vs. 39.3%, p&lt;0.01) and more cases of stage III CRC (60.9% vs 51.6%, p&lt;0.01). Adjusted by stage, patients with EOCRC were less likely to be MSI-H compared to patients with LOCRC (10% vs. 17%, p&lt;0.01), or have high tumor mutational burden (TMB-H) (15% vs. 19%, p&lt;0.01). Genes of the Hippo, NOTCH, WNT, and RTK-RAS oncogenic pathways were less commonly mutated in the EOCRC cohort (p&lt;0.01). The BRAF V600E mutation was less prevalent in the EOCRC group (3% vs. 15%, p&lt;0.01), regardless of TMB and MSI status. In the TMB-low/MSS group, TP53 mutations were more common in EOCRC (8% vs. 5%, p&lt;0.01), but APC gene mutations were less common in EOCRC (56% vs. 66%, p&lt;0.01). When comparing EOCRC and LOCRC in the TMB-H/MSI-H group, BRAF V600E (4% vs. 60%), RNF43 G659V (16% vs. 45%), and WNT1 G619A (6% vs. 20%) mutations were less prevalent in EOCRC (p&lt;0.01 for all mutations); however, patients with EOCRC had more mutations in PIK3CA H1047R (22% vs. 9%), APC R1468* (11% vs. 3%), and KRAS A146T (7% vs. 2%) gene variants (p&lt;0.01 for all mutations). In the TMB-H/MSS group, EOCRC patients were more likely to have driver mutations in the PI3K pathway (74% vs. 56%, p&lt;0.01). Further, POLE P286R mutations were more common in TMB-H/MSS patients with EOCRC compared to LOCRC (38% vs. 13%, p&lt;0.01), whereas ACVR2A K437R was less common (11% vs. 30%, p&lt;0.01).
Conclusion: Patients with LOCRC were more likely to have pathogenic gene variants and mutations in established pathways of CRC carcinogenesis. Tumors in EOCRC cases harbored unique genomic alterations that varied between the TMB-low/MSS, TMB-H/MSI-H, and TMB-H/MSS subpopulations.
Citation Format: Eric M. Lander, Samuel Rivero-Hinojosa, Vasily N. Aushev, Jesús Izaguirre-Carbonell, Adham Jurdi, Minetta C. Liu, Cathy Eng. Genomic alterations associated with early-onset and late-onset colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6696.