Sonabend, Rona

Abstract Background: Endocrine deficiencies are common following craniospinal irradiation (CSI) in children with brain tumors, but empirical data comparing outcomes following proton (PRT) and photon radiation therapy (XRT) are limited. Methods: This retrospective chart review compared the incidence of hypothyroidism, growth hormone deficiency (GHD), and adrenal insufficiency (AI) in patients with medulloblastoma treated with XRT and PRT between 1997 and 2016. All patients received CSI and had routine endocrine screening labs to evaluate for thyroid dysfunction, GHD, and AI. We used proportional hazards regression to calculate hazard ratios (HR) and 95% confidence intervals (CI) comparing the development of hypothyroidism, AI, and GHD between radiation modalities, adjusting for age at diagnosis, sex, race/ethnicity, and CSI dose.Results: We identified 118 patients with medulloblastoma who were followed for a median of 5.6 years from the end of radiotherapy. Thirty-five (31%) patients developed hypothyroidism, 71 (66%) GHD, and 20 (18%) AI. Compared to PRT, XRT was associated with a higher incidence of primary (28% vs. 6%; HR=4.61, 95% CI 1.2-17.7, p=0.03) and central hypothyroidism (33% vs. 9%; HR 2.35 (0.8-6.8, p=0.12). GHD and AI incidence rates were similar between the groups. Conclusions: Primary and central hypothyroidism occur less often after PRT CSI, compared to XRT CSI. This suggests that the thyroid and pituitary glands receive less radiation after spine and posterior fossa boost RT, respectively, using PRT.

10571 Background: Pediatric medulloblastoma patients exposed to craniospinal radiation (CSI) are at high risk of developing endocrinopathies, including hypothyroidism. We sought to evaluate the role of genetic variation on hypothyroidism susceptibility among survivors of pediatric medullobastoma. Methods: Records from 61 medulloblastoma survivors treated at Texas Children’s Hospital between 1997 and 2013 were reviewed. All patients completed baseline and yearly follow-up thyroid assessments. Genome-wide genotyping was performed on Illumina HumanOmni1 and HumanOmni2.5 BeadChip single nucleotide polymorphism (SNP) arrays. Following standard quality control measures and exclusion of rare variants (minor allele frequency [MAF] < 5%), 572,562 autosomal SNPs were included in our analyses. The association between each SNP and hypothyroidism was tested using Fisher’s exact test and logistic regression, assuming additive allelic effects. Results: A total of 25 patients (41%) developed hypothyroidism with median follow-up of 8.3 years from diagnosis (range: 1.8-17.2 years). Primary hypothyroidism was identified in 9 (36%) cases, while the remaining 16 (64%) developed central hypothyroidism. Hypothyroidism was detected in 13 of 40 (33%) individuals exposed to < 30 Gy CSI and 12 of 21 (57%) individuals exposed to ≥30 Gy CSI (p = 0.06). Genome-wide association analysis identified several risk loci, including 3 variants associated with hypothyroidism (p-value < 1x10-5) at chromosome 2q11.2 ( NPAS2 gene). The top overall SNP (MAF = 27.5%, p-value = 6.5x10-7) remained strongly associated with hypothyroidism after accounting for possible confounders, including CSI dose, CSI type (proton/photon), age, sex, and genetic ancestry. Conclusions: Our findings suggest susceptibility to treatment-related hypothyroidism is strongly influenced by common genetic variation in NPAS2. The NPAS2 gene, a central component of the circadian rhythm network, is a transcriptional activator and regulator of DNA damage response and DNA repair genes.