Decades can pass before signs of developing liver cancer appear to a patient or doctor, so early detection is critical. Pairing a unique understanding of cancerous genetic mutation patterns with cutting-edge lab technology, NIEHS-supported researchers at the Massachusetts Institute of Technology (MIT) documented early signs of liver cancer in mice.
Liver cancer is the third leading cause of cancer death worldwide. Though it may be possible to reduce chemical and viral risks for the disease, few symptoms appear until the late stage, when it is often too late to treat, said lead author Supawadee Chawanthayatham, Ph.D.
Liver cancer predicted by hot spots
The team was interested in aflatoxin B1, a fungal toxin often found in crop staples that is associated with impaired immune systems, malnutrition, and liver cancer. Scientists exposed very young mice to the toxin, and within 10 weeks they were able to view distinctive genetic mutation patterns, referred to as signatures, using a new, high resolution DNA sequencing tool.
“Even at 10 weeks, a very distinct mutational signature comes up,” said lead researcher John Essigmann, Ph.D., in an MIT press release. “It’s very early-onset, and you don’t see it with other carcinogens, to our knowledge.” Essigmann directs the NIEHS-funded MIT Center for Environmental Health Sciences.
Significantly, the signatures they saw in the young mice cells closely resembled those found in cancerous human liver cells that had been exposed to aflatoxin B1. Their study, published March 28 in the journal Proceedings of the National Academies of Sciences, laid the groundwork for establishing liver cancer exposure biomarkers.
“Points along the DNA sequence where mutation is likely to occur are called hot spots,” explained Chawanthayatham. “And when I first saw our early mutation spectrum with its large portion of DNA hot spots, I realized that we could use them as a biomarker to predict later-life disease.”
A novel part of the team’s sequencing protocol, developed by co-authors at the University of Washington, is how the tool links data from two complementary strands of DNA. With the two separate strands tagged and sequenced independently, true mutations can be spotted at the same site on each independent strand, and the error rate is greatly reduced.
A passion for early detection
The authors suggested the mouse model may be developed into a tool to detect early onset of human liver cancer and help manage the disease. They also hope to use their early detection approach to detect cancer mutational signatures of other environmental cancer-causing agents.
Chawanthayatham comes from Thailand, where a Thai-MIT study 50 years ago first connected aflatoxin in the environment with human liver cancer, a disease prevalent in that country. Her father died from the disease in 2016.
“I felt very bad because by the time his disease was clinically evident, it was too late to really help him,” she said. “It’s one of the reasons I have such a passion for early detection.”
“This timely and groundbreaking study is exciting to see,” added NIEHS Exposure, Response and Technology Branch Program Officer Carol Shreffler, Ph.D. “And it’s also gratifying to see it build on the landmark aflatoxin work done by MIT Drs. [Gerald] Wogan and Essigmann.”
Citation: Chawanthayatham S, Valentine CC, Fedeles BI, Fox EJ, Loeb LA, Levine SS, Slocum SL, Wogan GN, Croy RG, Essigmann JM. 2017. Mutational spectra of aflatoxin B1 in vivo establish biomarkers of exposure for human hepatocellular carcinoma. Proc Natl Acad Sci U S A, 114(15):E3101−E3109.
(Wendy Anson, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)