Sills leads the Cellular and Molecular Pathology Branch, which provides toxicologic pathology leadership support for NIEHS. (Photo courtesy of Steve McCaw)

Analyzing the entire genetic code of tumors in rodent cancer studies revealed that most rodent tumors had DNA mutation signatures that resemble those seen in human cancers, according to a new NIEHS study. A DNA mutation signature is the accumulation of cell mutations during the formation of a cancer.

The study of 20 chemicals previously linked with cancer found that only three had a DNA mutation signature in exposed mice that differed from those in aged, unexposed mice. The findings were published Sept. 28 in the journal Nature Genetics.

“DNA mutation signatures essentially document the life history of a cell by recording the fingerprints of past exposures and can help to decipher the mechanisms of cancer formation,” said Robert Sills, D.V.M, Ph.D., researcher at NIEHS who helped spearhead the international collaboration.

Scientists at NIEHS; the University of California, San Francisco; and the United Kingdom’s Wellcome Sanger Institute compared rodent and human tumor DNA mutation signatures. They observed that the same signatures present in rodent tumors — whether arising spontaneously or induced by chemicals — also occurred in human tumors.

“These are important findings in a time when we are concerned whether animal studies really provide human-relevant insights,” said Brian Berridge, D.V.M, Ph.D., scientific director of the Division of the National Toxicology Program. “The added value of this work is the potential for identifying DNA mutation signatures that might be modeled without animals.”

Cancer formation processes

“This study provides unique insights into potential pathogeneses of some chemically induced tumors and generates interesting hypotheses that we could explore in future studies,” said Berridge. (Photo courtesy of Steve McCaw)

Cancer formation can occur due to agents, such as ultraviolet light or tobacco, that directly damage DNA and lead to formation of tumors. The disease can also arise spontaneously from internal processes that go awry. Two such examples are defects in DNA repair systems and altered immune function due to aging, which fails to control abnormal cell growth.

To study the genetic mechanism of cancer formation, the researchers sequenced the DNA of lung and liver tumors from mice exposed to 20 chemicals designated as either “known,” “probable, “or “possible” carcinogens by the International Agency for Research on Cancer. They compared the DNA to that from normal tissues and from tumors that formed spontaneously during aging, or without chemical exposure.

Chemical, spontaneous tumors similar

The researchers pinpointed specific DNA mutation signatures within each tumor, finding that exposure to 17 of the chemicals caused signatures similar to tumors that arose spontaneously in the aged mice. Based on these observations, the authors suggested that chemicals promote tumor formation through mechanisms that build on existing cancer processes.

In contrast, DNA mutation signatures associated with exposures to cobalt, vinylidene chloride (VDC), and 1,2,3-trichloropropane (TCP) were different from the other tumors analyzed. Cobalt is primarily used to produce lithium-ion batteries. VDC was widely used in the 1980 to 1990s for the manufacture of Saran Wrap. TCP is a drinking water pollutant, part of a chemical group known as haloalkanes.

To understand the human relevance of mouse DNA mutation signatures, the researchers analyzed a collection of human cancers that contained nearly 24,000 sequenced tumors. They identified 76 human tumors whose mutation signatures were comparable to those seen in the exposed mice.

Pandiri leads the Molecular Pathology Group, which works to understand cancer processes in various organ systems resulting from exposures to environmental toxicants. (Photo courtesy of Steve McCaw)

“Our study provides new insight into environmental chemical carcinogenesis using a whole animal approach, although testing of additional rodent tumors resulting from exposure to various chemicals is necessary to draw definitive conclusions,” said NIEHS researcher Arun Pandiri, D.V.M, Ph.D., co-lead author of the study. “Further studies are needed to understand how chemicals promote tumors that arise spontaneously due to aging.”

Citation: Riva L, Pandiri AR, Li YR, Droop A, Hewinson J, Quail MA, Iyer V, Shepherd R, Herbert RA, Campbell PJ, Sills RC, Alexandrov LB, Balmain A, Adams DJ. 2020.The mutational signature profile of known and suspected human carcinogens in mice. Nat Genetics; doi:10.1038/s41588-020-0692-4 [Online 28 September 2020].