Adult survivors of childhood cancer have high rates of obesity, which, in combination with the cardiotoxic effects of specific cancer therapies, places them at high risk for cardiovascular morbidity. Here we show the contribution of genetic risk scores (GRSs) to increase prediction of those survivors of childhood cancer who are at risk for severe obesity (body mass index ≥40 kg m−2) as an adult. Among 2,548 individuals of European ancestry from the St. Jude Lifetime Cohort Study who were 5-year survivors of childhood cancer, the GRS was found to be associated with 53-fold-higher odds of severe obesity. Addition of GRSs to risk prediction models based on cancer treatment exposures and lifestyle factors significantly improved model prediction (area under the curve increased from 0.68 to 0.75, resulting in the identification of 4.3-times more high-risk survivors), which was independently validated in 6,064 individuals from the Childhood Cancer Survivor Study. Genetic predictors improve identification of patients who could benefit from heightened surveillance and interventions to mitigate the risk of severe obesity and associated cardio-metabolic complications.
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Aligned binary files for all the SJLIFE survivors and a subset of CCSS survivors whose childhood cancer was diagnosed between 1987 and 1999 and the joint genotype calls are accessible through the St. Jude Cloud (https://stjude.cloud). For CCSS survivors diagnosed between 1970 and 1986, genome-wide genotype data are available through the database of Genotypes and Phenotypes (accession number phs001327.v2.p1). Relevant phenotype data are available through the St. Jude Cloud for SJLIFE survivors and through https://ccss.stjude.org/ for CCSS survivors. Variant-level information used to calculate various GRSs examined in this study are available from previously published studies, including Turcot et al.16 (GRSrare), Khera et al.18 (GRScommon), Monda et al.61 (GRSAFR_8 and GRSAFR_179), Ng et al.62 (GRSAFR_genomewide), Vogelezang et al.22 (GRSchildhood_bmi), Bradfield et al.23 (GRSchildhood_obesity), Pulit et al.21 (GRSwhradjBMI) and Yengo et al.24 (GRS941). All data generated or analyzed during the study are included in the published article (and its supplementary files).
In-house scripts used to calculate AUC values and their CIs using 1,000 bootstrap iterations are available to download from https://github.com/sapkotagrp/NatMed2022_SevereObesity.
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The St. Jude Lifetime Cohort (U01 CA195547: M.M.H. and K.K.N.) and the Childhood Cancer Survivor Study (U24 CA55727; G.T.A.) are supported by the National Cancer Institute at the National Institutes of Health and the Cancer Center Support CORE grant (CA21765: C. Roberts). The CCSS original cohort genotyping was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. This work is also supported by R01 CA261898 (Y.S.) and R01 CA216354 (Y.Y. and J.Z.) from the National Cancer Institute at the National Institutes of Health and the American Lebanese Syrian Associated Charities in Memphis, Tennessee.
The authors declare no competing interests.
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Sapkota, Y., Qiu, W., Dixon, S.B. et al. Genetic risk score enhances the risk prediction of severe obesity in adult survivors of childhood cancer. Nat Med 28, 1590–1598 (2022). https://doi.org/10.1038/s41591-022-01902-3
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