Prevalence of Colorectal Cancer Molecular Profiles Is Not Captured by a Single Age Threshold

Early- and average-onset colorectal cancer (CRC) are separated at age 50, but whether this defines a biological threshold remains unclear. To clarify this, we identified molecular profiles in nine harmonised cBioPortal CRC cohorts (4,609 patients) by fitting Bernoulli mixture models to 31 repair-state, genomic-burden and gene-alteration features, excluding age, sex and tumour site, and compared their prevalence using <50/≥50 and decade-resolved groups. Four profiles captured conventional/CIN-like (P1), intermediate MSS (P2), KRAS/PI3K/APC-rich (P3) and hypermutated/MSI-high (P4) states along a left-to-right anatomical gradient. Although molecular identities remained stable, profile prevalence followed non-linear P1/P4 and opposing linear P2/P3 age trajectories. Profile prevalence patterns did not follow age distance: profile composition at 30-39 differed from 50-59 but not clearly from 40-49 or 60-69. The age-50 threshold captured only 17.8% of decade-resolved deviance, whereas the optimal age-70 cut-off retained only 51.3%. Validation in 2,235 non-overlapping MSK-IMPACT patients (2,134 age-evaluable) reproduced molecular-feature patterns (r=0.96-1.00), age trajectories (r=0.90) and limited binary-threshold performance: age 50 and the optimal age-75 cut-off retained 6.2% and 49.4%, respectively. Thus, age reorganises the prevalence of shared CRC states rather than defining a biological threshold at age 50.