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.

Methods

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.

Results

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.

Discussion

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.

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Corresponding Author: Megan Whitney, MSc, Department of Biology, University of Washington, PO Box 351800, Seattle, WA 98195 (megwhit@uw.edu).

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.</s>WASHINGTON (Reuters) - Scientists examining the jawbone of a saber-toothed, mammal-like beast that prowled Tanzania 255 million years ago have come across a remarkable fossil rarity: one of the oldest-known tumors.

A histological thin section of the gorgonopsid lower jaw of a saber-tooth mammal-like beast that prowled Tanzania 255 million years ago, taken near the top of the canine root showing the cluster of small circles, indicative of compound odontoma. Courtesy of Chistian Sidor/Megan Whitney/Handout via REUTERS

University of Washington researchers on Thursday described a benign tumor composed of miniature tooth-like structures they found embedded next to the root of the creature’s enlarged canine tooth while studying an unrelated aspect of the jaw.

The animal was a member of an extinct group of four-legged carnivores called gorgonopsians that mixed mammal-like and reptile-like traits. They reached up to 10 feet (3 meters) long and appeared early in the evolutionary lineage that led to mammals. The jawbone came from one of the smaller gorgonopsian species.

Gorgonopsians were among the top predators of their time, thriving from about 270 million to 252 million years ago when they were wiped out during Earth’s worst mass extinction at the end of the Permian Period. Their demise came roughly 20 million years before the first dinosaurs.

When the researchers sliced into the mandible fossil from Tanzania’s Ruhuhu Valley, they found a benign dental tumor called a compound odontoma that grows within the gums or other jaw soft tissues. When people get one, surgery is sometimes used to remove it.

“There was no indication that there was a tumor in this jaw. It looked normal before we cut it open. It was pure luck that we found the tumor,” University of Washington paleobiologist Megan Whitney said.

Until now, this type of tumor was known only in mammals, including some Ice Age fossils tens of thousands of years old. The new discovery shows such a tumor existed in mammal ancestors that lived tens of millions of years before the first mammals appeared.

Tumors, malignant and benign, typically involve soft tissue, and rarely fossilize.

“Ancient tumors generally need to affect hard parts such as bones and teeth in order to be preserved in the fossil record,” University of Washington paleobiologist Christian Sidor added.

This tumor included hard enamel and dentin.

Few tumor fossils are older. A 300-million-year-old fish was found with a tumor and a 350-million-year-old armored fish has an apparent tumor that some dispute.

“Fossils allow us to understand the evolution of diseases in deep time and have the potential to provide clues as to the causes of diseases that afflict humans,” Whitney said.

The research appears in the Journal of the American Medical Association Oncology.</s>A super-thin slice of the ancient gorgonopsid lower jaw fossil revealed the compound odontoma. Photo by Megan Whitney/Christian Sidor/University of Washington

SEATTLE, Dec. 8 (UPI) -- Researchers from the University of Washington have discovered the earliest evidence of a compound odontoma, a benign tumor made up of tiny tooth-like structures typically found growing in the gums.

Odontoma -- which are painful and typically surgically removed from the mouths of humans. -- are well known among mammals. Until now, however, the earliest evidence of the benign tumor came from ice age fossils.

The newest odontoma evidence was discovered in the 255 million-year-old lower jaw fossil of a gorgonopsid, a mammal predecessor. Scientists recalled the discovery in a new paper, published this week in the Journal of the American Medical Association Oncology.

"Until now, the earliest known occurrence of this tumor was about one million years ago, in fossil mammals," Judy Skog, program director in the National Science Foundation's Division of Earth Sciences, said in a news release. "The discovery suggests that the suspected cause of an odontoma isn't tied solely to traits in modern species, as had been thought."

Gorgonopsians fit beneath the umbrella of a larger group of animals called synapsids. Today, the only living synapsids are mammals.

"To understand when and how our mammalian features evolved, we have to study fossils of synapsids like the gorgonopsians," explained Megan Whitney, lead author and UW biology graduate student.

Synapsids are sometimes called reptile-mammals, as they posses features unique to both animal groups. Whitney and fellow graduate student Larry Mose were trying to study the similarities among the teeth of gorgonopsians, reptiles and mammals when they discovered the toothy mass.

"At first we didn't know what to make of it," said Whitney. "But after some investigation we realized this gorgonopsian had what looks like a textbook compound odontoma."</s>University of Washington researchers on Thursday described a benign tumor composed of miniature tooth-like structures they found embedded next to the root of the creature's enlarged canine tooth while studying an unrelated aspect of the jaw.

The animal was a member of an extinct group of four-legged carnivores called gorgonopsians that mixed mammal-like and reptile-like traits. They reached up to 10 feet (3 meters) long and appeared early in the evolutionary lineage that led to mammals. The jawbone came from one of the smaller gorgonopsian species.

Gorgonopsians were among the top predators of their time, thriving from about 270 million to 252 million years ago when they were wiped out during Earth's worst mass extinction at the end of the Permian Period. Their demise came roughly 20 million years before the first dinosaurs.

When the researchers sliced into the mandible fossil from Tanzania's Ruhuhu Valley, they found a benign dental tumor called a compound odontoma that grows within the gums or other jaw soft tissues. When people get one, surgery is sometimes used to remove it.

"There was no indication that there was a tumor in this jaw. It looked normal before we cut it open. It was pure luck that we found the tumor," University of Washington paleobiologist Megan Whitney said.

Until now, this type of tumor was known only in mammals, including some Ice Age fossils tens of thousands of years old. The new discovery shows such a tumor existed in mammal ancestors that lived tens of millions of years before the first mammals appeared.

"Ancient tumors generally need to affect hard parts such as bones and teeth in order to be preserved in the fossil record," University of Washington paleobiologist Christian Sidor added.

Few tumor fossils are older. A 300-million-year-old fish was found with a tumor and a 350-million-year-old armored fish has an apparent tumor that some dispute.

"Fossils allow us to understand the evolution of diseases in deep time and have the potential to provide clues as to the causes of diseases that afflict humans," Whitney said.

The research appears in the Journal of the American Medical Association Oncology.
University of Washington researchers report, in the peer-reviewed Journal of the American Medical Association Oncology, the discovery of an odontoma — a benign tumor — in the fossil of a 255-million-year old Tanzanian mammal-like saber-toothed gorgonopsia. This is one of the oldest-known tumors ever found.