Clinical Significance of Germline Telomere Length and Associated Genetic Factors in Patients with Neuroblastoma

Abstract

Background: Studies investigating the relationship between germline telomere length and the clinical characteristics of tumors are very limited. This study evaluated the relationship between germline telomere length and the clinical characteristics of neuroblastoma. In addition, a genome-wide association study (GWAS) was performed to investigate the genetic factors associated with telomere length. Methods: The telomere length of peripheral blood mononuclear cells from 186 patients with neuroblastoma was measured by quantitative PCR. The association between germline telomere length and clinical characteristics, including long-term survival, was investigated. For the GWAS, genotyping was performed with a high-density Illumina bead chip. After strict quality control checks of the samples, an association analysis was conducted. Results: An extra-abdominal primary site, lower stage (stage 1/2), MYCN non-amplified tumor, and being in the low-risk group were associated with longer telomere lengths (P = 0.015, 0.007, 0.046 and 0.042, respectively). Patients with longer third telomeres had longer event-free survival than other patients (P = 0.032). In the GWAS, rs2492082, located in the 3’UTR of the HIVEP3 gene, showed the highest association with telomere length (P = 1.7E-06). Patients with long telomeres had a recessive allele A. A gene-based analysis using the VEGAS2 algorithm showed that the CNTN4 gene had the most significant association with telomere length (P = 1.0E-06). Patients with the CC homozygote in the rs71311728 marker within the CNTN4 gene had a longer telomere length than those with the TC heterozygote. A gene ontology analysis showed that genetically susceptible genes associated with telomere length were mainly distributed in neurite morphogenesis and neuron development.Conclusions: Longer germline telomere length is associated with favorable prognostic factors at diagnosis and eventually better event-free survival in patients with neuroblastoma. In addition, the GWAS demonstrated that genetic markers and genes related to telomere length are associated with neurite morphogenesis and neuron development. A further study with a larger cohort of patients and functional studies are needed.