The Legacy Cell Hypothesis: Reactivation of Ancestral Genomic Programs as a Unified Mechanism of Oncogenesis

We propose a unified mechanistic model of cancer initiation grounded in three convergent processes typically treated as independent in the literature. First, reactive oxygen species (ROS) oxidatively damage methyl groups (CH3) at CpG sites of epigenetically silenced genomic sequences, causing loss of epigenetic silencing (hypomethylation). Second, the same or prior ROS events modify amino acid residues at binding sites of transcriptional signal factors, generating constitutively active or misdirected transcriptional commands. Third, the convergence of a corrupted transcriptional signal with a newly unlocked ancestral promoter initiates transcription of genomic sequences dormant in multicellular organisms for hundreds of millions of years. The resulting "legacy cell" synthesises an unpredictable mixture of atavistic proteins, bypasses apoptosis, and proliferates via geometric progression. The immune system cannot effectively target legacy cells: they carry valid MHC-I identity markers and their surface peptides have never been registered as a threat. NK cell capacity is fixed; legacy cell proliferation is not. The mathematical outcome is inevitable in the absence of intervention. The model generates testable, falsifiable predictions and invites experimental scrutiny.