International Journal of Osteoarchaeology Int. J. Osteoarchaeol. 9: 302–306 (1999) K-ras Mutation in the Tumour of King Ferrante I of Aragon (1431 – 1494) and Environmental Mutagens at the Aragonese Court of Naples GINO FORNACIARI*, ANTONIO MARCHETTI, SILVIA PELLEGRINI AND ROSALBA CIRANNI Department of Oncology, Division of Pathology, Section of Palaeopathology, University of Pisa, Pisa, Italy ABSTRACT 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 (glycine) 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. Copyright © 1999 John Wiley & Sons, Ltd. Key words: mummy; adenocarcinoma; DNA; oncogenesis; NOC; Renaissance Introduction The autopsy of the mummy of Ferrante I of Aragon, King of Naples and a leading figure of the Italian Renaissance, who died in 1494 at the age of 63 years (Figure 1), revealed a moder- ately differentiated adenocarcinoma of the colon, extensively infiltrating the muscles of the small pelvis. Histology showed exceptionally well-preserved neoplastic cells, disposed in cords and solid nests or forming pseudo-glandu- lar lumina (Figure 2), disseminated in a fibrous tissue containing striated muscular fibres. The cells appeared tall and crowded, with abundant cytoplasm and quite regular hyperchromatic nu- clei (Fornaciari et al., 1993). The excellent, almost exceptional, preserva- tion of the histological structure of this unique tumour is probably due to the very dry microcli- matic conditions of the church, and certainly to the preserving substances used in embalming (Fornaciari, 1998). As described in an ancient handbook on em- balming (Lanzoni, 1693), in Naples the bodies were washed with large quantities of aqua vitae and lye after being eviscerated; this treatment is likely to have ‘fixed’ the tissues, thus protecting their histological integrity. Furthermore, abun- dant vegetable resins poured into the cavities of the bodies, perfectly preserved the residual organs. * Correspondence to: Department of Oncology, University of Pisa, Via Roma, 57-56126 Pisa, Italy. Tel.: +390 50 992894; e-mail: g.fornaciari@do.med.unipi.it CCC 1047–482X/99/050302 – 05$17.50 Copyright © 1999 John Wiley & Sons, Ltd. Received 4 December 1998 Accepted 26 January 1999