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), TSH (TSHD), and ACTH (ACTHD) among survivors exposed to HP-RT.
Methods: Eligible participants included five-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 1,328 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% confidence interval 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.
Conclusions: 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.
Keywords: anterior-pituitary hormone; childhood cancer survivors; cranial radiation; hypothalamic-pituitary deficiency.
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