Estimating the carcinogenesis timelines in early-onset versus late-onset cancers and changes across birth cohorts.

Understanding when key mutations occur in cancer is critical for prevention and detection, especially for early-onset cancers that have risen in recent years. Yet, intermediate mutational steps remain difficult to observe. Here, we extend a tumor kinetic model and combine it with long-term cancer registry data to estimate mutational timelines. Using differential equation systems to represent sequential carcinogenic stages and a convolution-based method, we derive and estimate the expected ages of mutational transitions for breast, colorectal, and thyroid cancers. Model results suggest early-life initiations across all cancers. Malignant transitions occur ∼10 years earlier in early- vs late-onset breast and colorectal cancers (late 30s versus late 40s to 50s), while thyroid cancer shows similarly early transitions (late 20s) regardless of onset age. Across cohorts (1950-1954, 1965-1969, and 1980-1984), more recent cohorts show accelerated progression and earlier malignancy. These findings can inform early-onset cancer etiologic studies and intervention strategies.