Disruption of circadian rhythms is an emerging hallmark of cancer, yet whether somatic alterations in the core clock genes are subject to neutral stochastic processes or adaptive selection remains poorly defined. While complete circadian abrogation can cause genome instability and checkpoint-induced lethality, partial impairment might provide a context-dependent selective advantage by uncoupling cellular metabolic demand from environmental cycles. The somatic mutational landscape, 3D structural mapping, and clinical relevance of the 16 core circadian clock genes were systematically characterized across 10,239 human tumors representing 33 cancer types from The Cancer Genome Atlas (TCGA). A total of 2503 somatic mutation events were identified across 1294 mutated tumor samples (12.6% of pan-cancer cohort). Missense alterations dominated the mutational spectrum (61.2%, 1532/2503), with no deviation from the pan-cancer The Multi-Center Mutation Calling in Multiple Cancers (MC3) background rate (Z = -0.78, p = 0.44). In contrast to catastrophic inactivation, the clock genes were subject to selection at the level of preserved gene architecture. The highest absolute mutational burdens were concentrated in TIMELESS and Period family members (PER1, PER2, PER3) with missense variants mostly restricted to Uterine Corpus Endometrial Carcinoma (UCEC), Skin Cutaneous Melanoma (SKCM) and Colon Adenocarcinoma (COAD). Structural mapping highlighted the non-random accumulation of missense variants in heterodimerization interfaces, including the Per-Arnt-Sim (PAS) and basic helix-loop-helix (bHLH) domains, and in silico prediction identified a high proportion of deleterious substitutions. In survival modeling, associations between clock mutations and favorable prognosis were largely attenuated after multivariate adjustment for tumor mutational burden, highlighting potential lineage-specific confounding. In conclusion, somatic alterations in the mammalian circadian clockwork are predominantly non-synonymous substitutions that preserve overall gene architecture while altering conserved regulatory interfaces. These computational findings provide exploratory genomic observations consistent with the 'functional tuning' hypothesis, and raise the possibility of neoplastic cells selectively rewiring rather than completely abrogating circadian clock properties during oncogenesis.
