Early-onset colorectal cancer appears to share much of its genomic landscape with average-onset colorectal cancer, although certain molecular alterations may be enriched among younger patients, according to findings reported by Shin et al in JCO Precision Oncology. The investigators examined whether metastatic colorectal cancer diagnosed before age 50 represents a genomically distinct disease and assessed associations between age at diagnosis and recurrent genomic alterations.
Study Details
The analysis included 1,892 patients with histologically confirmed metastatic colorectal cancer who underwent next-generation sequencing as part of routine clinical practice at Samsung Medical Center between October 2019 and March 2025. Of these patients, 376 (19.9%) had early-onset colorectal cancer and 1,516 had average-onset colorectal cancer. The median ages were 44 and 62 years, respectively. Among patients with early-onset disease, 71% were aged 40 to 49 years and 24% were aged 30 to 39 years.
Tumor samples were evaluated using two targeted next-generation sequencing assays, the TruSight Oncology 500 and Oncomine Comprehensive Assay Plus. The investigators compared genomic alteration frequencies between the early-onset and average-onset colorectal cancer groups and performed age-stratified analyses to assess relationships between age at diagnosis and recurrent genomic alterations. Tumor mutational burden and microsatellite instability were also evaluated.
Key Results
Overall, the genomic landscapes of early-onset and average-onset colorectal cancer were largely similar. Frequencies of the major colorectal cancer driver alterations did not differ significantly between groups: TP53 alterations were detected in 78.5% of early-onset vs 77.4% of average-onset colorectal cancer (P = .652), APC alterations in 69.9% vs 70.8% (P = .732), and KRAS alterations in 46.5% vs 48.9% (P = .417). BRCA2 alterations were also comparable (25.3% vs 24.6%; P = .790), as were BARD1 alterations (24.2% vs 27.2%; P = .233). In contrast, MYC alterations were significantly more frequent among patients with early-onset colorectal cancer (15.7%; P = .012).
Tumors with high mutational burden were observed in 14.6% of patients with early-onset colorectal cancer and 19.3% of those with average-onset disease. Tumors with high microsatellite instability occurred in 2.7% and 1.7% of the early-onset and average-onset colorectal cancer groups, respectively. Among patients with microsatellite-stable early-onset colorectal cancer, alterations were dominated by the canonical chromosomal instability drivers TP53, APC, and KRAS, whereas tumors with high microsatellite instability displayed a more dispersed genomic profile.
Age-stratified analyses identified additional differences that were not apparent when patients were divided simply into early- and average-onset groups. Within the early-onset cohort, younger age was significantly associated with higher alteration rates in BRCA2 (P = .0304), BARD1 (P = .0159), FAT1 (P = .025), HIST1H1C (P = .0102), and LRP1B (P = .0117). Alteration rates for these genes progressively declined with increasing age. In contrast, TP53, APC, KRAS, ARID1B, and NOTCH3 showed no significant age-dependent associations.
The investigators concluded: “In metastatic disease, [early-onset colorectal cancer] shares a conserved canonical genomic backbone with [average-onset colorectal cancer], indicating that it is not a genomically distinct entity. Nevertheless, limited binary differences involving MYC and broader age-dependent enrichment of specific DNA damage response–related alterations suggest that [colorectal cancer] arising at younger age may reflect distinct age-associated biological vulnerabilities.”
Seung Tae Kim, MD, PhD, of Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea and Samsung Precision Genome Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea, is the corresponding author for the JCO Precision Oncology article.
DISCLOSURE: The study was supported by Korea Health Technology R&D Project through the Korea Health Industry Development Institute, and by the Ministry of Health & Welfare, Republic of Korea. For full disclosures of the study authors, visit ascopubs.org.
