K-ras mutation in the tumour of King Ferrante I of Aragon (1431-1494) and environmental mutagens at the Aragonese Court of Naples

The autopsy of the mummy of Ferrante I of Aragon, King of Naples (1431-1494) revealed an adenocarcinoma extensively infiltrating the muscles of the small pelvis. A molecular study of neoplastic tissue observed a typical mutation of the K-ras gene codon 12: the normal sequence GGT (qlycine) was altered into GAT (aspartic acid). The recorded genetic change represents the most frequent mutation of the K-ras gene in sporadic colorectal cancer and is characteristic of the effects of alkylating agents. Recent studies have focused the importance of some alkylating agents such as the endogenous N-nitroso compounds (NOC). Increased intake of red meat, such as beef, lamb or pork, induces a significant threefold increase of faecal NOC levels, with a range of exposure in faeces similar to that from tobacco-specific NOC in cigarette smoke. The study of alimentary regimens of the Italian Renaissance courts, and in particular of the Aragonese court of Naples, produced evidence of very high red meat consumption, attested also by the palaeonutritional data. Therefore, the alimentary 'environment' of the Neapolitan court of the 15th century with the abundance of natural endogenous alkylating agents, can well explain the K-ras mutation causing the tumour that killed the Aragonese king over five centuries ago.