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Genetic Risk Score Increases Prediction of Severe Obesity in Adult Survivors of Childhood Cancer

Genetic testing, along with assessment of clinical risk factors, could be used to identify survivors at high risk for severe obesity and associated cardio-metabolic complications
05 Aug 2022
Cancer in Special Situations / Population;  Translational research

A report from large cohorts of adult survivors of childhood cancer demonstrates that genetic risk scores improve the risk prediction of developing severe obesity, providing opportunities for surveillance and mitigation interventions. Among 2,548 individuals of European ancestry from the St. Jude Lifetime Cohort Study who were 5-year survivors of childhood cancer, the genetic risk score was associated with 53-fold-higher odds of severe obesity. Addition of genetic risk scores to risk prediction models based on cancer treatment exposures and lifestyle factors significantly improved model prediction, which was independently validated in 6,064 individuals from the Childhood Cancer Survivor Study. The findings are published by Yadav Sapkota, PhD of the St. Jude Children’s Research Hospital in Memphis, TN, USA and colleagues on 25 July 2022 in the Nature Medicine.

The authors wrote in the background that adult, long-term survivors of childhood cancer are at significantly increased risk of multiple chronic health conditions related to late toxicities of cancer treatment, which increases with age. Aging survivors also develop modifiable risk factors, such as obesity, further potentiating the risk of many chronic health conditions, including hypertension, diabetes and cardiovascular disease, which contribute to premature mortality. Early identification of survivors at risk of preventable risk factors is important and provides opportunity for targeted interventions. In survivors of childhood cancer, an increased risk of obesity is associated with exposure to cranial radiation therapy, total body irradiation, corticosteroids, reduced physical activity, low energy expenditure during exercise and pre-existing childhood obesity.

Although obesity is often thought to be primarily linked with unhealthy lifestyle choices, obesity is also known to be heritable, suggesting the role of genetic susceptibility. Large-scale genome-wide association studies have implicated both rare and common variants associated with body mass index (BMI). Although many studies have identified risk factors for obesity among survivors of childhood cancer, a prediction model for this outcome has not been developed. The prevalence and predictors of severe obesity among survivors of childhood cancer are also currently unknown. The purpose of this study was to characterise severe obesity among long-term survivors of childhood cancer using the St. Jude Lifetime cohort and to develop and validate clinically applicable prediction models that identify survivors at high risk for severe obesity based on patient characteristics, cancer treatment and inherited genetic variation.

Among St. Jude Lifetime Cohort Study survivors of European ancestry in the training cohort (52.8% male), the median age at BMI measurement was 29.9 years, 29.7% received cranial radiation, and 48.0% were treated with glucocorticoids. Nearly one-fifth were exposed to abdominal (19.0%), chest (22.2%) or pelvic (16.6%) radiation. Among St. Jude Lifetime Cohort Study survivors of European ancestry, 27.7% had overweight, 28.4% had obesity, and 7.3% had severe obesity. The corresponding prevalences in the Childhood Cancer Survivor Study validation cohort were 27.0%, 12.7% and 2.2%. Consistent with previous reports, higher prevalence of obesity was observed among survivors of acute lymphoblastic leukaemia.

Among St. Jude Lifetime Cohort Study survivors of European ancestry, the univariable polytomous logistic regression adjusted for age at BMI assessment and the top ten principal components identified male sex; irradiation to brain, chest, pelvis, abdomen and hypothalamus–pituitary axis; exposure to glucocorticoids; smoking; and physical activity as significant predictors for at least one of the BMI categories. In the multivariable polytomous logistic regression analysis, severe obesity was positively associated with exposure to glucocorticoids, and negatively associated with being a current smoker compared to never smoking status and higher physical activity. Obesity was negatively associated with exposure to chest radiation, being a current smoker as compared to those who never smoked and higher physical activity. Compared to female sex, male sex was associated with higher risk of obesity and overweight. Exposure to pelvic radiation was associated with higher risk of underweight.

The study team showed the contribution of genetic risk scores to increase prediction of adult survivors of childhood cancer who are at risk for severe obesity. Among 2,548 individuals of European ancestry from the St. Jude Lifetime Cohort Study who were 5-year survivors of childhood cancer, the genetic risk score was associated with 53-fold-higher odds of severe obesity. Addition of genetic risk scores to risk prediction models based on cancer treatment exposures and lifestyle factors significantly improved model prediction, as 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.

Using the two largest cohorts of adult survivors of childhood cancer in North America, the study team developed and validated a prediction model that can be used to identify young survivors at high risk of severe obesity. Similarly to the prediction models for other late effects, such as congestive heart failure and stroke in survivors, the predictive ability of the comprehensive prediction model, including clinical, treatment, lifestyle and genetic risk factors, provided good to fair discrimination between survivors with and without severe obesity. The authors concluded that the use of genetic risk factors enabled identification of substantially more survivors with high predicted odds of severe obesity than the model with clinical risk factors alone.

The St. Jude Lifetime Cohort and the Childhood Cancer Survivor Study are supported by the US National Cancer Institute at the US National Institutes of Health and the Cancer Center Support CORE grant. The Childhood Cancer Survivor Study original cohort genotyping was supported by the Intramural Research Program of the US National Cancer Institute, US National Institutes of Health. This work is also supported by the American Lebanese Syrian Associated Charities in Memphis, Tennessee.

Reference

Sapkota Y, Qiu W, Dixon SB, et al. Genetic risk score enhances the risk prediction of severe obesity in adult survivors of childhood cancer. Nature Medicine; Published online 25 July 2022. DOI: https://doi.org/10.1038/s41591-022-01902-3

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