studies that support the relationship between genetic risk variants and type 2 diabetes in childhood cancer survivors. They have also found that exposure to alkylating agents can further increase the risk of developing diabetes. This research highlights the importance of considering an individual’s ancestry when assessing their genetic risk for type 2 diabetes, especially in populations of non-European descent. By understanding how ancestry influences the impact of genetic risk variants, healthcare providers can better tailor diabetes prevention and management strategies for childhood cancer survivors.The Journal of Clinical Oncology published a study that discovered previously unknown genetic variants linked to the risk of diabetes in all survivors. The research also revealed a connection between a genetic risk score for type 2 diabetes in the general population and the risk of diabetes in survivors. Additionally, the findings offered new insights into the differences in risk among individuals of different ancestries.
The study was based on the St. Jude Lifetime cohort study (St. Jude LIFE), which is a long-term follow-up study for individuals who were treated for cancer as children. This cohort allowed the researchers to identify the four unknown genetic variants associated with diabetes risk in survivors.”We identified previously unknown genetic variations that are more common in people of African descent than in those of European ancestry,” the researchers explained. They also discovered that polygenic risk scores derived from diverse ancestry datasets were more effective in assessing diabetes risk in individuals of both European and African ancestries compared to those derived from the general population of European ancestry. Additionally, they noted that all genetic risks for diabetes were intensified by childhood exposure to alkylating agents, a type of chemotherapy. “Our findings show that survivors carry DNA variants that elevate the risk of type 2 diabetes,” co-author of the study stated.Senior and lead author Yadav Sapkota, PhD, from the St. Jude Department of Epidemiology and Cancer Control, stated, “For survivors who were exposed to alkylating agents, certain genetic variations are associated with varying levels of risk based on their ancestry. This may help to explain some of the disparity in the burden of type 2 diabetes among survivors.”
Childhood cancer survivors have a threefold higher risk of developing type 2 diabetes compared to their siblings. However, non-Hispanic Black survivors are at three times higher risk compared to non-Hispanic white survivors. To understand these differences, the researchers conducted whole genome sequencing on the patients from the study.
Researchers from the St. Jude LIFE cohort conducted a study that compared the DNA of childhood cancer survivors with type 2 diabetes to those without the condition, and they categorized the participants by their ancestry. The study resulted in a valuable collection of combined clinical and genetic data.
The study found that the genetic risk for type 2 diabetes was more pronounced in survivors of African or African American ancestry who had been previously treated with alkylating agents. Lead researcher Sapkota explained that the same genetic variant was linked to type 2 diabetes in both European and African-ancestry groups, but the level of risk associated with carrying the variant varied between the two groups.
To address this disparity in more depth, researchers compared previously reported polygenic risk scores for diabetes in the general population. Previous studies had used a large number of genetic variants, grouped together, to determine the risk of developing the disease. However, these risk scores were typically based on individuals of European descent. The researchers compared three risk scores: a traditional score based solely on individuals of European descent, and two others that included people of different ancestries. The more inclusive scores performed better in individuals of both European and African ancestries.The study found that two risk scores based on multiple ancestries were significantly linked to the risk of type 2 diabetes in survivors of diverse ancestries, compared to the score developed only using European ancestry,” Sapkota explained. Additionally, the research also indicated that exposure to alkylating agents, a type of chemotherapy frequently used in childhood cancer treatments, can also contribute to an increased risk of type 2 diabetes. Out of the four identified variants and all polygenic risk scores, a significant increase in diabetes risk was consistently observed.There is an increased risk of type 2 diabetes in survivors who were exposed to alkylating agents during their initial treatment,” Sapkota explained. “Genetic factors combined with alkylating agents can significantly raise the risk of developing type 2 diabetes.”
The impact of alkylating agents was also found to be more pronounced in individuals of African descent. Although the reasons for these differences in risk are not fully understood, the study represents a step towards addressing them.
“We hope that this information will help reduce disparities in the burden of type 2 diabetes,” Sapkota stated. “Now that we understand how to identify childhood cancer survivors who are at the highest risk of developing type 2 diabetes, we can offer more targeted support.The study emphasizes the importance of personalized interventions to prevent cardiovascular complications in the future. The first author of the study is Cindy Im from the University of Minnesota, and the co-senior author is Carmen Wilson from St. Jude. The study also includes other authors from various institutions such as the Fred Hutchinson Research Center, Children’s Hospital of Philadelphia, Baylor College of Medicine, and the University of Alabama at Birmingham.Angela Delaney, Stephanie Dixon, Gregory Armstrong, Melissa Hudson, Kirsten Ness, Leslie Robison and Yutaka Yasui, all from St. Jude, conducted the study.
The study received funding from the National Cancer Institute (R21 CA261833, R01 CA261898, R01 CA216354, U01 CA195547, U24 CA55727, and CA21765), Children’s Cancer Research Fund, University of Minnesota Foundation Pediatric Scholar Award, and ALSAC, which is the fundraising and awareness organization of St. Jude.
Â
