Bone Abstracts (2015) 4 OP6 | DOI: 10.1530/boneabs.4.OP6

Genetic variation is involved in impairment of bone mineral density in long-term adult survivors of childhood cancer

M A H den Hoed1,3, S M F Pluijm1,3, L Stolk2, A G Uiterlinden2, R Pieters3 & M M van den Heuvel-Eibrink1,3

1Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children’s Hospital Rotterdam, Rotterdam, The Netherlands; 2Department of Internal Medicine, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands; 3Princess Maxima Center for pediatric Oncology, Utrecht, The Netherlands.

Introduction: 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 adult 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), BMDTB was associated with previously administered radiotherapy(P=0.01). Survivors with the homozygous minor allele (GG) genotype of rs2504063 (in ESR1: estrogen receptor type 1) had a lower BMDTB (−1.17 vs −0.84; P=0.01) than those with the AG/AA genotype, however BMDLS was not altered. Carriers of two minor alleles (GG) 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/TG genotype. Carriers of VDR (vitamin D receptor) haplotype 3 had a lower BMDLS than non-carriers (−0.86 vs −0.64, P=0.05), but BMDTB was not altered.

Conclusion: CCS who are carriers of candidate SNPs in the VDR, ESR1 or LRP5 genes seem to be more vulnerable to impaired bone mass at an early adult age. In addition to patient and treatment related factors, information on genetic variation in cancer patients may be helpful in identifying survivors who are at risk for low bone density after childhood cancer treatment.

Disclosure: The authors declared no competing interests.

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