Abstract Background: The Prime-Fibonacci-Square (PFS) framework classifies the 22 autosomal chromosomes based on their mathematical properties. Chromosomes at positions that are both Prime and Fibonacci (2, 3, 5, 13) or both Fibonacci and Square (1) are designated "STRUCTURED" positions, representing 5 of 22 chromosomes (22.7%). Methods: We analyzed 1,850,105 somatic mutations from the COSMIC v103 database across 30 distinct cancer types. For each cancer type, we calculated the proportion of mutations occurring on STRUCTURED versus NEUTRAL chromosomes and compared to the expected uniform distribution. Results: 29 of 30 cancer types (96.7%) showed mutation rates at STRUCTURED positions exceeding the expected 22.7%. The average across all cancer types was 33.35%, representing a 10.65 percentage point excess (47% relative increase). This pattern held across anatomically and histologically diverse cancers including kidney (44.69%), brain (38.91%), liver (37.06%), breast (36.27%), and blood (30.80%). Conclusions: Cancer mutations show a universal preference for chromosomes at mathematically STRUCTURED positions. This pattern suggests that genes critical for cellular function cluster on these chromosomes, and their disruption through mutation drives oncogenesis. The PFS framework may provide a new mathematical lens for understanding cancer genetics. Keywords: COSMIC database, somatic mutations, chromosomal distribution, mathematical biology, Prime-Fibonacci-Square framework, cancer genetics