The National Toxicology Program (NTP) Archives is contributing rodent tumor samples to a new $24.4 million study of the links between human cancers and specific environmental factors. The project is one of four winners of the Cancer Research United Kingdom (CRUK) Grand Challenge, announced Feb. 10.
The researchers will examine human and animal cancers for unique patterns of genetic mutations that may result from chemical exposures. These characteristic patterns are called mutational signatures, also known as mutational fingerprints. Along with expertise in rodent pathology, NTP is providing tumor and normal tissue samples from carefully documented studies of rats and mice that were exposed to more than 100 chemical carcinogens. The researchers will compare mutational fingerprints from the rodent tumors with those from human cancer tissues.
“We hope that this innovative study using the NTP Archives will help scientists better understand how substances in our environment lead to cancer,” said NTP Associate Director John Bucher, Ph.D.
Determining environmental causes of cancer
The NTP Archives are part of a project titled “Identifying Preventable Causes of Cancer” led by Professor Sir Mike Stratton, M.D., Ph.D., director of the Wellcome Trust Sanger Institute (WTSI). Collaborators include scientists from the United States, United Kingdom, and France. He presented the concept behind the project during a Jan. 12 lecture at NIEHS.
The study builds on initial evidence that certain environmental factors, such as ultraviolet radiation and tobacco, leave a distinct mutational fingerprint when they damage the DNA in our cells. Currently, at least 50 mutational fingerprints have been identified, but only about half have been linked to specific environmental factors.
Stratton’s team will study mutational fingerprints from 5,000 pancreatic, kidney, esophageal, and colorectal cancer samples from around the world, comparing them with mutational fingerprints from samples in the NTP Archives and other data. This is the most comprehensive attempt to compare animal and human cancer mutation signatures in relation to chemical exposures.
“The main aim of our Grand Challenge is to understand the causes of cancer. Every cancer retains an archaeological trace, a record in its DNA, of what caused it. It’s that record that we want to explore to find out what caused the cancer,” Stratton said in a press release.
The project addresses one of seven major cancer research challenges identified by the CRUK Grand Challenge committee — to discover how unusual patterns of mutation are induced by different cancer-causing events. Other challenges include distinguishing between lethal cancers that need treatment and nonlethal cancers that do not, and mapping tumors at the molecular and cellular levels to inform diagnosis and treatment. The nonprofit CRUK invited scientists from around the world to submit innovative research proposals to address these challenges.
NTP Archives provide a unique resource
Allan Balmain, Ph.D., from the University of California at San Francisco, is collaborating with Stratton on the CRUK grant. He initially approached Robert Sills, D.V.M., Ph.D., who heads the NTP Cellular and Molecular Pathology Branch, to collaborate on a project to identify mutational signatures and understand molecular pathways in chemically induced rodent tumors.
Sills and colleagues have an ongoing collaboration with Balmain and Dave Adams, Ph.D., from WTSI, to examine the genomic and epigenomic changes in chemically induced rodent lung tumors induced by chemical exposure. Sills said he expects that the changes in rodent tumors will be relevant to human disease.
The CRUK Grand Challenge grant increases the scale of these collaborations and aims to sequence a large number of rodent tumors from various environmental exposures. Arun Pandiri, Ph.D., head of the NTP Molecular Pathology Group, is coordinating the pathology evaluation and sample selection from the NTP Archives. He said that he hopes that this project will spark wider use of the NTP Archives. Pandiri noted that each of the 100 NTP studies involved exposures of both male and female rats and mice for 13-week and 2-year durations.
Ron Herbert, D.V.M., Ph.D., oversees the archives. He said they are an unmatched collection of publicly available research specimens, detailed documentation from chemical exposures, and pathology assessments, all of which make the NTP Archives especially useful for toxicology research.
(Virginia Guidry, Ph.D., is a technical writer and public information specialist in the NIEHS Office of Communications and Public Liaison, and a regular contributor to the Environmental Factor.)