Localized variation in ancestral admixture identifies pilocytic astrocytoma risk loci among Latino children

Background: Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. PA has at least a 50% higher incidence in populations of European ancestry compared to other ancestral groups, which may be due in part to genetic differences. Methods: We first compared the global proportions of European, African, and Amerindian ancestries in 301 PA cases and 1185 controls of self-identified Latino ethnicity from the California Biobank. We then conducted admixture mapping analysis to assess PA risk with local ancestry. Results: We found PA cases had a significantly higher proportion of global European ancestry than controls (case median = 0.55, control median = 0.51, P value = 3.5x10-3). Admixture mapping identified 13 SNPs in the 6q14.3 region (SNX14) contributing to risk, as well as three other peaks approaching significance on chromosomes 7, 10 and 13. Downstream fine mapping in these regions revealed several SNPs potentially contributing to childhood PA risk. Conclusions: There is a significant difference in genomic ancestry associated with Latino PA risk and several genomic loci potentially mediating this risk. Author summary: Childhood brain tumors are among the most prevalent and lethal childhood cancers. Despite this, the epidemiology as well as genetic risks are not well defined. For example, children of European ancestry have a higher risk of contracting pilocytic astrocytoma (PA) compared to other ancestries, but the genetic or environmental basis for this is unknown. Latino children are a mixture of multiple ancestries including European, African, and Native American. Using a group of Californian Latino children, we show that the risk of PA increases when a Latino child has a higher proportion of European ancestry. This global ancestry difference shows that germline genetic risk alleles contribute to a higher PA risk in children of European descendent. Moreover, this ancestral risk is localized to specific regions of the genome, especially in Chromosome 6 near the SNX14 gene, which is associated with cancer-related growth signaling pathway described by MAPK/ERK. This result brings us one step closer to understanding the etiology of this common childhood brain tumor.