Simple Summary
Incidence of colorectal cancer among individuals under the age of 50, defined as early-onset colorectal cancer (eoCRC), is increasing. However, the factors driving this are unclear at this time. We assessed the somatic and germline mutational profiles of patients with early-onset and average-onset colorectal cancer (aoCRC, diagnosed at age ≥ 50 years). We found that among 11,006 patients who completed somatic profiling, the most frequently observed somatic mutations included APC, TP53, and KRAS, and the most significant difference between eoCRC and aoCRC was higher rates of BRAF mutation among patients with aoCRC. Among 6311 patients who completed germline testing, pathogenic germline variants were discovered in 6.9% of patients with eoCRC and 5.0% of patients with aoCRC. Overall, somatic and germline profiles among those with eoCRC and aoCRC were similar, and do not adequately explain differences in tumor behavior and age of disease onset.

Abstract
Background: Rates of early-onset colorectal cancer (eoCRC), defined as disease diagnosed at <50 years of age, are increasing. The incidence and spectrum of somatic and pathogenic germline variants (PGV) in this population are not well understood. Methods: This cross-sectional study leveraged Tempus’ clinicogenomic database, including de-identified records of patients diagnosed with CRC between 2000–2022, to analyze and compare eoCRC and average-onset colorectal cancer (aoCRC, disease diagnosed ≥50 years of age) patients. The frequency and spectrum of somatic mutations and PGVs in patients with eoCRC and aoCRC were evaluated and compared. Results: Among 11,006 participants in this study, 57% were male, 76% were white, and 80% had stage 4 disease. Within the total cohort, 2379 had eoCRC and 8627 had aoCRC. Among patients with eoCRC, 4.2% had a tumor with high microsatellite instability and/or deficient mismatch repair (MSI-H/dMMR) and 6.8% with aoCRC had an MSI-H/dMMR tumor (p < 0.001). The most frequent somatic mutations involved TP53, APC, and KRAS, with the most significant difference in BRAF, which was more frequently mutated in aoCRC (9.8% vs. 4.7%, p < 0.0001). In total, 1413 (59.4%) eoCRC and 4898 (56.8%) aoCRC patients had matched normal specimen (blood or saliva) sequencing and a PGV was identified in 6.9% of eoCRC and 5.0% of aoCRC patients. Conclusions: Somatic and germline mutation profiles were similar for eoCRC and aoCRC patients and may not adequately explain differences in tumor behavior and age of disease onset.

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