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Genetic risk score enhances the risk prediction of severe obesity in adult survivors of childhood cancer

Abstract

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 m2) 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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Fig. 1: BMI and its categories in survivors of childhood cancer and community controls.
Fig. 2: Genetic risk prediction of obesity and severe obesity in survivors of childhood cancer.

Data availability

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).

Code availability

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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Acknowledgements

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.

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Authors

Contributions

Y.S. and Y.Y. designed the study. S.B.D., C.L.W., Z.W., J.Z., W.L., E.J.C., S.B., G.T.A., L.L.R., M.M.H. and A.D. assisted in, or provided support for, data collection and recruitment of study participants. Y.S. and Y.Y. developed the statistical analysis plan. Y.S., W.Q. and Y.Y. performed the statistical analyses. Y.S. drafted the manuscript. All authors contributed to data interpretation and manuscript revision and approved the final version for publication.

Corresponding authors

Correspondence to Yadav Sapkota or Yutaka Yasui.

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The authors declare no competing interests.

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Nature Medicine thanks Struan Grant and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary handling editor: Anna Maria Ranzoni, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Table 1 Demographic and clinical characteristics of African American survivors of childhood cancer in the St. Jude Lifetime Cohort
Extended Data Table 2 Distribution of childhood cancer diagnoses by BMI categories among European American survivors in the St. Jude Lifetime Cohort and the Childhood Cancer Survivor Study
Extended Data Table 3 Distribution of childhood cancer diagnoses by BMI categories among African American survivors in the St. Jude Lifetime Cohort
Extended Data Table 4 Multivariable polytomous logistic regression model for obesity among European American survivors of childhood cancer in the St. Jude Lifetime Cohort, using the GRSrare_v2 based on the same 12 rare/low-frequency variants used for the analysis in the Childhood Cancer Survivor Study
Extended Data Table 5 AUC estimates for predicting overweight or higher, obesity or higher and severe obesity among European American and African American survivors
Extended Data Table 6 AUC estimates for predicting overweight or higher, obesity or higher and severe obesity among survivors of childhood cancer, further including age at cancer diagnosis in the prediction models
Extended Data Table 7 Multivariable polytomous logistic regression model for obesity among European American survivors of childhood cancer in the St. Jude Lifetime Cohort, further including the genetic risk score for waist-to-hip ratio adjusted for BMI
Extended Data Table 8 Multivariable polytomous logistic regression model for obesity among European American survivors of childhood cancer in the St. Jude Lifetime Cohort, further including the genetic risk score for childhood BMI
Extended Data Table 9 Multivariable polytomous logistic regression model for obesity among European American survivors of childhood cancer in the St. Jude Lifetime Cohort, further including the genetic risk score for childhood obesity
Extended Data Table 10 Multivariable polytomous logistic regression model for obesity among European American survivors of childhood cancer in the St. Jude Lifetime Cohort, further including the genetic risk scores for waist-to-hip ratio adjusted for BMI, childhood BMI and childhood obesity

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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 (2022). https://doi.org/10.1038/s41591-022-01902-3

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