Distinctive mammalian traits, such as endothermy (warm-bloodedness), a muscular diaphragm, large brain size, fur, and a highly specialized dentition, including diphyodonty, prismatic enamel, and a functionally regionalized tooth row (heterodonty), are the product of more than 300 million years of evolutionary divergence from reptiles and other tetrapods.1 The sequence and timing of these adaptations are captured in the fossil record of premammalian synapsids (Figure 1), but an understanding of the evolutionary context of mammalian disease, including cancer, remains elusive. We report the first instance, to our knowledge, of a tumor in a 255-million-year-old mammalian forebear and comment on the implications for establishing the phylogenetic and physiological conditions under which such pathologic features first arose.
Fossil thin-sectioning protocol is well established, and the resultant data are an increasingly significant tool in understanding the physiologic mechanisms and evolution of extinct animals.2 Despite the relative abundance of gorgonopsian fossils, few histologic observations have been made of their jaws. The anterior right dentary of a gorgonopsian was prepared by embedding the specimen in a clear polyester resin. Thin (approximately 2 cm) wafers of the embedded specimen were cut using a precision slow-speed saw and then mounted onto glass slides. Sections were ground to a final thickness of approximately 100 µm using a variable-speed grinder and polisher. The root of the lower canine and associated pathological tissues were examined and imaged under regular and cross-polarized light.
Institutional review board approval was waived for this study because no live specimens were used.
Histologic sections present ectopic toothlike structures that were not apparent from the external morphologic features of the mandible (Figure 2). The lesions are located adjacent to the labial edge of the functional canine root, and each resembles a miniature tooth with an internal cavity, dentine as evidenced by the presence of tubules, and a thin outer covering of enamel. Up to 8 lesions of varying diameter (approximately 0.3-3.9 mm) can be observed on an individual slide, with consecutive slides revealing that their shape and arrangement change along the apical-cervical axis of the canine root. Apically, the lesions are circular and cluster around the mesial edge of the canine root. Incursion of the lesions into the root of the canine coincides with the loss of cementum and dentine in the latter. Moving cervically, the masses erode even further into the functional tooth root. Midroot, some of the lesions lose their circular cross-sectional shape and become more amorphous, although continuing to maintain similar tissues and tissue boundaries. Near the cervical region of the canine root, the lesions slightly retreat from their incursion and penetrate further into the bone of the jaw. At this cervical end, the pathologic features return to a circular cross-section and cluster together.
Histologic examination reveals that this ancient condition closely resembles compound odontoma.3 In humans, compound odontoma is characterized by fully differentiated enamel and dentine organized into miniature teeth that can cause resorption of the functional tooth root,3 all of which mirror our paleohistologic observations. Odontomas are the most common odontogenic tumors,3 but their cause is poorly understood. Interestingly, odontomas have been reported in a handful of fossil mammals up to a few million years old4,5 but were previously unknown in deep premammalian evolutionary history. Recognition of odontoma in such a distant relative of humans suggests that this condition is unlikely related to characteristics of mammalian dentition or physiologic features but rather evolved much earlier in vertebrate evolution. More broadly, the fossil record has the potential to provide an evolutionary context for modern pathologic features6 by disassociating traits that co-occur in modern species.
Corresponding Author: Megan Whitney, MSc, Department of Biology, University of Washington, PO Box 351800, Seattle, WA 98195 (email@example.com).
Published Online: December 8, 2016. doi:10.1001/jamaoncol.2016.5417
Author Contributions: Ms Whitney and Dr Sidor had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Whitney, Sidor.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: All authors.
Obtained funding: Sidor.
Administrative, technical, or material support: Sidor.
Study supervision: Sidor.
Conflict of Interest Disclosures: None reported.
Funding/Support: This research was supported by grant EAR 1337569 from the National Science Foundation (Dr Sidor) and a University of Washington Mary Gates Research Fellowship (Mr Mose).
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.
Disclaimer: The views in this article are those of the authors and do not represent official positions of the University of Washington.
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