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Under the Microscope: Brightening the outlook for childhood cancer survivors

Thanks to new treatments, survival rates for children with cancer are high. However, the treatments they receive put them at higher risk for a variety of chronic health conditions later in life — a risk that is unfortunately amplified for those with socioeconomic disadvantages.

With V Foundation funding, Zhaoming Wang, Ph.D., and I-Chan Huang, Ph.D., from St. Jude Children’s Research Hospital are working to better understand the role of socioeconomic status in health problems among adult survivors of childhood cancer. This work could lead to new ways to help these survivors stay healthy throughout their lives.

“Most cancer survivorship research focuses on documenting the long-term toxicity of cancer treatment,” explained Wang. “We are among the first to look at the biological causes of health disparities in childhood cancer survivors. This group is vulnerable because they age faster, which means that chronic health conditions affect them even earlier. Someone who had cancer treatment as a child might have a heart attack in their thirties, for example.”

In pioneering new work, the researchers are using the concept of social epigenetics to study how social factors and cancer treatment work together to change the way a person’s genes are expressed. By helping to reveal the biological mechanisms behind these disparities, researchers hope to find ways to identify those at highest risk and intervene to reduce or prevent the chronic health conditions they face.

A unique clinical resource

The new research draws on the St. Jude Lifetime Cohort, a clinical cohort St. Jude Children’s Research Hospital established to follow its pediatric cancer patients over their lifetimes. The approximately 6,000 patients and survivors currently enrolled in the cohort visit the clinic every few years for comprehensive medical assessments that include blood draws, physical performance tests, neuro-psychological assessments and more.

“Our study wouldn’t be possible without the data from this group of patients, which is one of the largest cohorts of this type in the country,” said Huang. “Thanks to the extensive assessments, we are able to examine more than 175 chronic health conditions, assess various socioeconomic factors and also conduct epigenetics analyses on stored blood samples.”

The researchers are studying a particular type of epigenetic change — a change to the genome that affects how genes are expressed — known as DNA methylation. For the first part of their project, they examined how cancer treatments affect DNA methylation and, subsequently, chronic health conditions. As published in a Genome Medicine paper, they identified thousands of DNA methylation sites that were affected by cancer treatment, especially radiation.

“This shows that the treatment leaves a permanent signature on the epigenome,” said Wang. “We also found that some of these changes are linked to cardiometabolic conditions, which helps explain why the treatment increases the risk of chronic health conditions.”

Next, they examined how each person’s education level, personal and household income, and neighborhood disadvantaged socioeconomic status correlated with DNA methylation patterns. For this study, published in an Epigenetics paper, they measured DNA methylation at about 1 million sites and found around 130 DNA methylation sites were correlated with these socioeconomic factors. For example, people with higher education had very different methylation signatures than those with less education. The researchers then began to take a closer look at these 130 socioeconomically linked markers to see if any were linked with chronic health conditions. This ongoing research suggests that some of these markers may mediate the association between socioeconomic factors and impaired lung function.

Closing the disparity gap

The research could eventually be used to help identify people at high risk of certain conditions, to develop interventions aimed at modifying socioeconomic exposures, and possibly even develop drugs that target the genes involved in these disparities.

“These methylation signatures can also be used to measure how well interventions are working,” said Wang. “Changes in epigenetics are immediately accessible, which means we don’t have to wait and see if patients go on to develop a chronic disease to find out if an intervention is working.”

Next, the researchers plan to use RNA sequencing to study how methylation levels relate to expression levels for individual genes, uncovering more information about the biological mechanisms at work. They are also applying for NIH grants to extend their work and develop interventions that could help improve the unmet social needs of childhood cancer survivors with the aim of counteracting certain health disparities in this vulnerable population.