6715 Short Adult Height in Childhood Cancer Survivors: Prevalence, Risk Factors, and Genetic Contribution

Abstract

Abstract Disclosure: T. Yoshida: None. J. Baedke: None. F. Wang: None. W. Moon: None. Y. Sapkota: None. J. Miguel Martínez: None. T.E. Merchant: None. C.L. Wilson: None. K.K. Ness: None. M.M. Hudson: None. Y. Yasui: None. A. Delaney: None. Background: Survivors of childhood cancer are at elevated risk for short adult height (SAH) due to cancer and/or its treatment. In the general population, height is a highly polygenic trait; heritability is estimated to be 70-80%. However, the contribution of genetic factors to SAH among childhood cancer survivors is unknown. In addition, the contribution of chemotherapy agents to risk of SAH among survivors has not been established. We assessed: 1) prevalence of SAH; 2) contribution of genetic factors; and 3) impact of cancer therapy including chemotherapy, on SAH in a large cohort of childhood cancer survivors. Methods: Participants included 4461 childhood cancer survivors aged ≥18 years (female 47.5%, mean age 33.2 years old) with measured height information. SAH was defined as height <3rd percentile for age and sex based on the Centers for Disease Control growth charts. Cancer and treatment history were extracted from medical records. We calculated multi-ancestry height polygenic score (PGS) using the latest methodology developed from 5.4 million individuals of diverse ancestries with more than 1 million variants, where lower score associates with shorter height. With a random sample of 75% of survivors, we fit a multivariable logistic regression model for SAH with the PGS, chemotherapy exposures/doses, corticosteroid exposures/doses, and established risk factors for SAH (e.g., age at cancer diagnosis, radiotherapy exposure) as covariates (main model). The remaining 25% of survivors served for validation of the main model and for the calculation of the population attributable fractions (PAF) of the PGS and cancer treatments. Results: The prevalence of SAH was 8.9% among all survivors (9.3% in males; 8.5% in females) and differed widely by primary cancer diagnosis. SAH was associated with lower PGS [odds ratio (OR) 0.47, 95% confidence interval (CI) 0.40-0.55 for a one standard deviation increase], alkylating agent exposure of >12000 mg/m2 (OR 2.19, 95% CI 1.41-3.38, vs. non-exposure), and spinal radiotherapy (OR 3.65, 95% CI 2.23-6.00, vs. non-exposure). Radiotherapy exposure to the hypothalamic-pituitary region and younger age at cancer diagnosis was also associated with SAH in a dose-response manner. The area under the ROC curve of the main model in the validation dataset was 0.80 (95% CI 0.74-0.87), suggesting good predictive ability for SAH by the model. The PAF of SAH calculated from the multiplicative logistic regression model of SAH was 85.7% for cancer treatments and 30.2% and 60.2% for having PGS below the median and the 90th percentile, respectively. Conclusions: Cancer treatments are the primary contributor to SAH risk among survivors with a PAF of 85.7%. Exposure to high-dose alkylating agents contributes to this along with radiotherapy. Inherited genetic factors also affect SAH among survivors but to a much lesser degree than cancer treatments. Presentation: 6/3/2024