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  • Genetic Variants and Diabetes Risk in Childhood Cancer Survivors

    Identifying Genetic Links Through Cohort Studies
    In a significant study from St. Jude Children's Research Hospital, published in the Journal of Clinical Oncology, researchers have discovered four new genetic variants that influence the risk of developing type 2 diabetes in survivors of childhood cancer. These findings underscore the complex interplay between genetic factors and the lasting effects of cancer treatments. The research utilized the St. Jude Lifetime cohort study (St. Jude LIFE), a comprehensive long-term follow-up project for individuals treated for cancer during childhood. This extensive study provided a crucial foundation for comparing genetic sequences and health outcomes among childhood cancer survivors.

    Genetic Variants More Common Among African Descent
    The newly identified genetic variants were found to be more prevalent in individuals of African descent compared to those of European ancestry. Yadav Sapkota, PhD, co-senior and corresponding author from the St. Jude Department of Epidemiology and Cancer Control, highlighted the significance of these findings. "We found DNA variants in survivors that increase the risk of type 2 diabetes," Sapkota stated. “Among survivors exposed to alkylating agents, these variants are conferring differential risk based on the ancestry, which may partially explain some of the disparity in type 2 diabetes burden in survivors.”

    Whole Genome Sequencing Reveals Crucial Differences
    To delve deeper into these disparities, the team performed whole genome sequencing on participants from the St. Jude LIFE cohort. By comparing the genetic information of survivors who developed type 2 diabetes with those who did not, researchers could pinpoint differences that might explain the increased susceptibility to diabetes.

    “The genetic risk disproportionately affected survivors of African or African American ancestry previously treated with alkylating agents,” explained Sapkota. “The same variant is implicated in both European and African-ancestry groups, but the amount of risk conferred by carrying the variant differs.”

    The researchers then examined the relevance of polygenic risk scores traditionally used to assess diabetes risk in the general population. These scores, which had been predominantly derived from European genetic data, were less effective at predicting diabetes in survivors from diverse ancestries. By incorporating genetic data from multiple ancestries, the researchers developed more robust risk scores. Sapkota noted, "The two risk scores derived from multiple ancestries were strongly associated with type 2 diabetes risk in survivors of diverse ancestries compared to the score developed in European-only ancestry."

    Chemotherapy's Role in Amplifying Diabetes Risk
    The research also demonstrated that exposure to alkylating agents during initial cancer treatment significantly raises the risk of developing diabetes later in life. "We saw very consistently, in three out of our four identified variants, and all of our polygenic risk scores, a significant increase in diabetes risk when survivors were exposed to alkylating agents during their initial treatment," remarked Sapkota. This correlation points to a complex interaction between genetic predispositions and specific chemotherapy treatments, highlighting a greater impact on those of African ancestry.

    Future Directions
    This study's implications extend beyond understanding genetic risks, aiming to better tailor interventions for childhood cancer survivors. "We hope this information will help reduce disparities in the type 2 diabetes burden," concluded Sapkota, pointing towards the potential for more personalized healthcare strategies to mitigate cardiovascular risks associated with diabetes in this vulnerable population.

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