Abstract 853: The role of germline microRNA-related polymorphisms on pediatric medulloblastoma prognosis and survival

Abstract

Abstract Background: Five-year survival for pediatric medulloblastoma is between 60-80%, which remains far from ideal. While the molecular features of these tumors are being used to improve risk stratification, novel markers are needed to identify those at the greatest risk of recurrence and poor survival. MicroRNAs (miRNA) regulate gene expression and may play a major role in regulatory networks related to cancer therapy. Because of that, single nucleotide polymorphisms (SNPs) within these regions (miR-SNPs), which have the ability to alter normal miRNA function, are being evaluated in terms of cancer prognosis and survival. However, to our knowledge, miR-SNPs have not been evaluated in terms of outcomes (recurrence and survival) among those with pediatric medulloblastoma. Methods: Patients with medulloblastoma (n = 100) treated at Texas Children's Cancer Center and MD Anderson Cancer Center between 1982 and 2009 who had existing genotype data from the Illumina Omni1 array were included in this analysis. We selected 25 miR-SNPs within 24 genes with a minor allele frequency (MAF) greater than 5%. Variants were selected from within pri- or pre-miRNAs, miRNA processing machinery, or within binding sites identified in the literature as related to tumorigenesis. The remaining variants were predicted to create or destroy miRNA binding sites per the prediction algorithm PolymiRTS 3.0. Adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) were calculated using Cox regression under log-additive or dominant genetic models (if the MAF fell between 5-15%) to estimate the association between miR-SNPs and progression-free and overall survival (OS) times. All models were adjusted for sex (reference = male), race (reference = white), and age at diagnosis (continuous). Clinical variables including risk group, and craniospinal radiation were also analyzed. Multiple comparisons were adjusted for using the false discovery rate method. Results: The median follow-up time among 88 survivors was 8.33 years (range 1.16 - 25.83 years). Individuals who carry a copy of the minor allele of KIAA0423 (rs1053667), which is located within a putative miR-19a/b binding site, experienced 2.93 times the hazard of progression (CC+CT vs. TT: aHR = 2.93; 95% CI: 1.10-7.83). For overall survival, carriers of a copy of the minor allele experienced 3.96 times the hazard of death (CC+CT vs. TT: aHR = 3.96; 95% CI: 1.12-14.02). While these data point to a potentially strong effect, the results did not remain significant after adjustment for multiple comparisons. Conclusions: This preliminary analysis suggests that certain miR-SNPs may be associated with pediatric medulloblastoma recurrence and survival; however our findings must be validated in a larger population. Validated miR-SNPs may potentially be used for refined risk stratification for those diagnosed with childhood cancers or may be informative for targeted therapies. Citation Format: Erin C. Peckham, Philip J. Lupo, Austin L. Brown, Mehmet Fatih Okcu, Ching C. Lau, Surya Rednam, Michael E. Scheurer. The role of germline microRNA-related polymorphisms on pediatric medulloblastoma prognosis and survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 853. doi:10.1158/1538-7445.AM2015-853