Background: Despite similarities in upfront treatment, impairment of bone mineral density (BMD) varies in long-term adult survivors of childhood cancer (CCS). We studied for the first time whether genetic variation is involved in impairment of BMD in adult long-term CCS.
Method: This cross-sectional single-center cohort study included 334 CCS (median follow-up time: 15.2 years [range 5.1-39.8]; median age at follow-up: 26.1 years [range 18.1-49.3]). Total body BMD (BMDTB) and lumbar spine BMD (BMDLS) were measured by dual-X-ray absorptiometry(DXA), and BMD was expressed as age-matched and gender-matched standard deviation scores (SDS;Z-score). We selected 12 candidate single nucleotide polymorphisms(SNPs) in 11 genes based on results of previous studies in the healthy population (COL1A1, TNFSF11, TNFRSF11, TNRFSA11B, VDR, ESR1, WLS, LRP5, MTHFR, MTRR, IL6). Multivariate analyses included apart from candidate SNPs, patient and treatment characteristics that were univariatly associated with BMD values.
Results: Multivariate analyses revealed that lower BMDTB/LS was associated with lower weight at follow-up (p<0.01) and BMDTB with previously administered radiotherapy (p=0.01). Survivors with the homozygous minor allele (CC) genotype of rs2504063 (in ESR1: oestrogen receptor type 1) had a lower BMDTB(-1.17 vs. -0.84; p=0.01) than those with the TT/CT genotype, but BMDLS was not altered. Carriers of the homozygous minor allele (CC) genotype of rs599083 (LRP5: low-density lipoprotein receptor) revealed lower BMDTB (-1.18 vs. -083; p=0.04), and lower BMDLS values (-0.97 vs. -0.54; p=0.02) than those with the TT/CT genotype.
Conclusions: We showed that CCS who are carriers of candidate SNPs in the ESR1 or LRP5 genes are more vulnerable to loss of bone mass at an early adult age. Information on genetic factors variation in individual patients may be helpful in identifying survivors who are at risk for low bone density after childhood cancer treatment in addition to patient and treatment related factors.
Disclosure: The authors declared no competing interests. S.P. is supported by the Paediatric Oncology Centre Society for Research (KOCR), Rotterdam, The Netherlands.