Could DNA be linked to premature aging in cancer survivors?

In this interview, we talk to Dr. Zhaoming Wang about his latest research on accelerated aging in childhood cancer survivors and the underlying genetics that cause it.

Could you introduce yourself and tell us what inspired your latest research?

I am an associate faculty member at St. Jude Children’s Research Hospital, with a primary appointment in the Department of Epidemiology and Cancer Control and a secondary appointment in the Department of Computational Biology. My research on biomarkers of aging was originally inspired by my colleague, Dr. Kiri Ness, who was one of the first to report the phenomenon of accelerated aging in childhood cancer survivors.

Over the past two years, we have collaborated and published our research demonstrating that biomarkers of aging, including leukocyte telomere length (https://aacrjournals.org/clincancerres/article/26/10/2362/82443/ Shortened-Leukocyte-Telomere-Length -Associates) and epigenetic age (https://academic.oup.com/jnci/article-abstract/113/5/597/5911122?redirectedFrom=fulltext&login=false) are involved in the age acceleration. This latest publication is the third in the line of my targeted research on aging.

Although the majority of children in the United States survive cancer, some children may develop diseases typically seen in older adults and the reason why this occurs is not fully understood. Why is it?

On average, age-related chronic health problems occur much earlier in survivors than in the general non-cancer population. For example, a survivor at age 35 may be comparable to a non-cancer individual at age 50 with respect to the risk of developing cardiovascular disease. However, not all survivors showed the same level of accelerated aging and therefore the same risk.

We use a biomarker of aging (e.g. epigenetic age) to objectively measure the biological age of each survivor and try to show that biological aging can explain the difference from one survivor to another in terms of development of age-related chronic diseases.

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You have previously assessed the non-genetic risk factors for this accelerated aging. What did you discover from this previous research and why did your team choose to focus this time on the underlying genetic factors?

Our previous research has shown that previous exposures to cancer treatments and health behaviors affect accelerated aging. These are non-genetic factors and can be used to identify survivors with higher accelerated aging. For example, a survivor previously treated with radiation to the chest or having adopted an unhealthy lifestyle.

From the literature we know that biological aging is also partially determined by hereditary genetics. So we conducted this research to look for genetic factors. In the future, we may use both genetic and non-genetic factors to improve the accuracy of identifying survivors with higher accelerated aging.

In your latest research, you studied accelerated aging in childhood cancer survivors. Can you describe how you carried out your latest research and what you discovered?

We leveraged pre-existing whole genome sequencing data and used a genome-wide association study (GWAS) approach to agnostically search for genetic variations strongly correlated with epigenetic age acceleration. .

We identified two statistically significant genetic markers, one mapped to the SELP gene that codes for P-selectin, and the other mapped to the HLA region that codes for genes important for immune functions.

In your research, you used data from childhood cancer survivors enrolled in the St. Jude Lifetime Cohort Study (SJLIFE). How important are data sets like this to furthering our understanding of illness and disease?

It is extremely important to have a resource such as the St. Jude Lifetime Cohort Study to allow researchers to do survival research so that we can understand the long-term effects of treatment toxicity, accelerated aging trajectories, as well as the pathophysiology of chronic disease development. .

What effects does this accelerated chronological age have on these pediatric cancer survivors?

Accelerated aging will lead to early onset of age-related chronic health problems and premature mortality in childhood cancer survivors.

St. Jude Cloud: A Pediatric Genomics Data Resource for the Scientific Community

Do you believe your research could be used to help us identify high-risk survivors of accelerated aging before symptoms develop? What advantages does this have not only for healthcare professionals but also for the patients themselves?

Yes. However, we would need to expand our research from a single time point to multiple time points (i.e. measuring epigenetic age and chronic health conditions longitudinally) to provide supporting evidence. of the temporal association. This will ultimately enable the realization of precision preventive medicine allowing healthcare professionals to discuss and implement intervention strategies with patients to slow the aging process and therefore prevent age-related diseases.

Are the results of your latest study publicly available for other St. Jude Cloud researchers? Why did you decide to make your results publicly available? What advantages does this have for accelerating future research?

The data we generated and used in this study is available to the scientific community, so other colleagues in the same field could access the data to develop new methods and perform their own analysis.

St. Jude Cloud has been a great platform for sharing our data which is not only easily accessible but also ensures that our patients’ privacy is properly protected.

The ongoing COVID-19 pandemic has highlighted the importance of collaboration within research. How important was collaboration in this research?

This project was initiated and completed during the pandemic. Most of those involved had to work remotely. It is indeed quite difficult, but we accomplished it by working together virtually. Research like this requires different expertise, and we have assembled a multidisciplinary team including an epidemiologist, computational biologist and biostatistician.

What are the next steps in your research?

We plan to conduct further observational studies to examine whether biomarkers of aging can be predictive of lifespan and health in childhood cancer survivors. We also plan to design intervention trials targeting biomarkers of aging.

I foresee that this could ultimately lead to a paradigm shift in survivorship research and care: focusing on aging and extending lifespan instead of compressing a specific chronic disease.

About Dr Zhaoming Wang

I am currently co-chair of the Genetics and Genomics Task Force of the Cancer Control and Survival Program at St. Jude Children’s Research Hospital Cancer Center. My research has focused on three related but progressive areas: 1) the genetic epidemiology of cancers (primary and subsequent); 2) Discovery of biomarkers for late effects in childhood cancer survivors, and 3) Omics-based precision preventive medicine.Dr Wang

I established myself as an expert in germline cancer genetics during my tenure as the bioinformatics group leader in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. One of my most significant contributions to the field of cancer epidemiology and genetics is the design of the OncoArray for the Genetic Associations and Mechanisms in Oncology consortium in 2013, which led to a series of major publications around 2017.

After joining St. Jude in 2015, I expanded research on biomarkers of aging in childhood cancer survivors who experience accelerated aging and who suffer from a high burden of chronic diseases related to treatment and aging. In 2018, I led the groundbreaking publication on genetic susceptibility to second cancers in the Journal of Clinical Oncology and followed with a second major article on monogenic and polygenic risk of later breast cancer in Clinical Cancer Research. Since 2007, I have authored over 190 publications with over 30,000 citations.

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