PDTM-33. EUROPEAN GENETIC ANCESTRY ASSOCIATED WITH RISK OF CHILDHOOD EPENDYMOMA

Abstract

Abstract BACKGROUND Ependymoma is a histologically-defined central nervous system tumor most commonly occurring in children. Incidence differs by race/ethnicity, with individuals of European ancestry at highest risk. No large-scale genomic analyses of ependymoma predisposition have been conducted to date. We aimed to determine whether extent of European genetic ancestry is associated with ependymoma risk. METHODS In a multi-ethnic study of Californian children (327 cases, 1970 controls), we estimated the proportions of European, African, and Native American ancestry among admixed Hispanic and African-American subjects and estimated European substructure among non-Hispanic white subjects using genome-wide data. We tested whether genome-wide ancestry differences were associated with ependymoma risk and performed admixture mapping to identify associations with local European ancestry. We also re-analyzed CBTRUS data to examine subtype-specific differences in ependymoma incidence across racial/ethnic groups. RESULTS Each 20% increase in European ancestry was associated with 1.31-fold greater odds of ependymoma among Hispanic and African-American subjects (95% CI: 1.08–1.59, Pmeta=6.7×10–3). Among non-Hispanic whites, European ancestral substructure was also significantly associated with ependymoma risk. Local admixture mapping revealed a peak at 20p13 associated with increased local European ancestry, and genotype association analysis in the region identified an association upstream of R-spondin 4 that survived Bonferroni correction (P=2.2x10-5) but was not validated in an independent set of posterior fossa type A (PF-EPN-A) patients. In complementary CBTRUS analyses, American Indian/Alaskan Natives were at reduced risk relative to non-Hispanic whites (RR=0.64, 95% CI:0.46–0.87), as were African-Americans (RR=0.67, 95% CI:0.60–0.74) and Asian/Pacific Islanders (RR=0.86, 95% CI:0.73–1.00). Although overall ependymoma rates were similar in U.S. Hispanics (RR=0.96, 95% CI:0.88–1.05), lower rates were observed for myxopapillary ependymoma and other spinal ependymoma. CONCLUSION Inter-ethnic differences in ependymoma risk vary by histopathologic and potentially molecular subgroup, and are recapitulated in the genomic ancestry of ependymoma patients.