NCI’s CURE Distinguished Scholar discusses epigenetics of liver cancer
In her presentation at the NCI’s Continuing Umbrella of Research Experiences Distinguished Scholars Seminar, Cathrine Hoyo, PhD, MPH, recalled a study that would influence the course of her career.
“As soon as I got my K01 funding and began to implement my specific aims, I came across a journal article by Randy Jirtle, PhD, that showed, for the first time, that when you manipulate nutrition, you can actually change the epigenome,” said Hoyo, professor of epidemiology in the department of biological sciences and co-director of the Integrated Health Sciences Facility Core in Center for Human Health and the Environment at North Carolina State University. “So, because I had the K01 and had 5 years ahead of me, I decided to go to Dr. Jirtle’s lab and learn. He welcomed me into his lab.”
Hoyo’s work during those years helped shape the nature of her future research, which relates to the role of early environmental factors in altering development and health outcomes.
“What that K01 led to were two distinct but related topics that we continue to pursue in our lab today,” said Hoyo, who serves as director of the epidemiology and environmental epigenomics laboratory at North Carolina State University. “One is looking at the developmental origins of adult disease in general, and the other is looking at disparities in environmental exposures and how these influence metabolic disorders and cancer.”
Hoyo’s achievements were profiled in CURE’s semiannual scientific seminar series, which recognizes the contributions of former CURE K01 recipients in the fields of cancer and health disparities research.
“Dr. Hoyo and her team are conducting cutting-edge research in molecular biology, genomics and epidemiology,” Mary Ann S. Van Duyn, PhD, MPH, associate deputy director for integration within the NCI’s Center to Reduce Cancer Health Disparities, said in her introduction of Hoyo. “Her pioneering research is helping to enhance our ability to pinpoint epigenetic targets that contribute to racial differences in the incidence and mortality of diseases, including cancer.”
Early exposures and risk
Hoyo discussed her research team’s two-pronged approach to understanding the effects of early developmental exposures on chronic disease risk. She described the Developmental Origins of Health and Disease (DOHAD) framework, which maintains that the environment during preconception, pregnancy and infancy impacts the adult disease phenotype and ultimately disease risk.
“How this would work is that the early exposure, such as to toxic metals like cadmium, is recorded as a molecular alteration at susceptible loci,” Hoyo said. “It tends to be retained, so you can find it if you know what you’re looking for. And that expression is not just the transcriptional potential; it actually orchestrates disease.”
Hoyo cited the Dutch Famine of 1944 to 1945. Early exposure to severe caloric restriction during the famine was found to be correlated with increased risk for metabolic syndrome and cancer, depending on the sex of the child and the trimester during which they were exposed.
“If it was much later in life, the diseases tended to be different, like schizophrenia,” she said.
Hoyo discussed the NEST study, in which her team assessed a cohort of newborns from the first trimester to identify potential epigenetic targets. They looked at various risk factors and how they might influence DNA methylation profiles in newborns, as well as health outcomes later.
“The idea was to look at suspected risk factors for cancer or other chronic disease, and look at the phenotypes that occur,” she said. “We then characterized the epigenomic response to those exposures to see which of them are stable enough to be used as biomarkers for cancer and other chronic diseases much later.”
In the NEST study, the researchers enrolled more than 2,500 pregnant women at approximately 8 to 12 weeks’ gestation. They enrolled a diverse population of women residing in Durham County, North Carolina.
The researchers evaluated maternal blood concentrations of 24 different metals and assessed these concentrations in relation to where the women lived. They found geographic clusters of women with elevated concentrations of cadmium and lead. The clusters were seen in Durham County’s lower-income communities.
Cadmium has been found to have toxic effects on various organs, and more toxicities are being discovered, Hoyo said. She said researchers are currently exploring the social determinants of environmental pollutant exposure, potential dietary interventions and manipulation of the microbiome to chelate metals.
The liver cancer connection
Hoyo and her group then looked at the potential connection between early environmental exposure to toxic metals and the incidence of liver cancer.
“The question becomes: What about liver cancer?” Hoyo said. “This is one of the fastest-increasing cancers; it disproportionately affects Black and Hispanic patients. Case fatalities are high and the known risk factors do not explain the disparities and the increases in incidence.”
Hoyo cited a study that showed the same low-income, predominantly minority-populated “cadmium cluster” ZIP codes of Durham County also had higher rates of liver cancer. This correlation was not seen in other cancers they evaluated. They began to consider the degree to which the epigenetic marks specific to liver cancer and those specific to cadmium overlap.
Effect on DNA methylation
Hoyo’s group studied the effects of cadmium exposures on DNA methylation at imprint control regions (ICRs) and genome-wide in a population consisting equally of Black and white participants. They found 1,945 differentially methylated regions in mothers and 641 in their newborn children.
“This shows an early acquired epigenetic mark that was driven by an environmental exposure,” she said.
Hoyo discussed another analysis of the NEST cohort, which sought to understand the relationship between cadmium exposure and MEG3 methylation differences between white and Black individuals.
“We have seen the relationship between hypermethylation of that MEG3 region and cadmium exposure very early in life,” she said. “If you divide that based on ethnicity, you realize that it is being driven only by being African American. No other population seems to have this hypermethylation.”
Hoyo and her group then studied the application of ICR methylation profiling to early detection of liver cancer. Specifically, they tested the hypothesis that early exposure to cadmium increases liver cancer risk through detectable epigenetic shifts at ICRs. However, because 80% of hepatocellular carcinoma is diagnosed radiographically, they had difficulty obtaining resected biopsies for African Americans. These patients tend not to have tissue available for analysis.
In the future, Hoyo said her research team plans to build a multiethnic case control study for liver cancer, identify epigenetic shifts in acceptable tissues and cell types that may contribute to liver cancer, and identify epigenetic marks prompted by environmental contaminants.
“The other area we are excited about is validating these ICRs so we can share this with the research community,” she said. “We then want to develop custom arrays that can be shared with everyone as we look at the developmental origins of adult disease.”