Hypothalamic-pituitary deficiency after radiation in childhood cancer survivors is associated with rare variants in TNS2.
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CONTEXT: Radiation to the hypothalamic-pituitary (HP) region (HP-RT) is a strong risk factor for HP deficiency among childhood cancer survivors (survivors). However, there is inter-individual variability in developing HP deficiency after similar HP-RT dose exposures. OBJECTIVES: To assess the genetic contribution to developing deficiencies of GH (GHD), LH/FSH (LH/FSHD), thyroid-stimulating hormone deficiency (thyroid-stimulating hormone deficiency [TSHD]), and ACTH (adrenocorticotropic hormone deficiency [ACTHD]) among survivors exposed to HP-RT. METHODS: Eligible participants included 5-year survivors exposed to HP-RT (n = 809; median follow-up 31.9 years) from the St. Jude Lifetime Cohort. We assessed the association between rare variants from whole-exome sequencing data (minor allele frequency [MAF] < 0.01, predicted to be pathogenic by functional prediction tools) and HP deficiency rate (total counts/person-year) among 801 survivors by the exact Poisson test. Genome-wide association analysis (GWAS) was conducted among 606 survivors of European ancestry with available whole-genome sequence data, targeting variants with MAF ≥ 0.01. The replication population was 1328 survivors from the Childhood Cancer Survivor Study (CCSS). RESULTS: Carriers of rare variants in TNS2, a ubiquitously expressed protein-coding gene including in brain, had significantly higher rates of HP deficiencies (rate ratio 2.72 [95% CI 1.81-4.09], P = 1.5 × 10-5) compared to non-carriers, which was replicated in the CCSS. This was also observed in individual HP deficiencies: LH/FSHD (3.31 [1.28-7.99]), TSHD (5.29 [2.42-11.34]), and ACTHD (3.97 [1.05-12.31]). There were no statistically significant variants in GWAS. CONCLUSION: TNS2 may contribute to radiation-induced HP deficiencies. With further validation, screening for TNS2 variants has potential to help identify individuals who would benefit from surveillance and intervention following HP-RT.