Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma

Abstract

John Maris and colleagues identify common variants at 6q16 associated with neuroblastoma susceptibility. The risk variants are located near the HACE1 and LIN28B genes, both of which show altered expression in advanced neuroblastomas. Neuroblastoma is a cancer of the sympathetic nervous system that accounts for approximately 10% of all pediatric oncology deaths1. Here, we report a genome-wide association study of 2,817 neuroblastoma cases and 7,473 controls. We identified two new associations at 6q16, the first within HACE1 (rs4336470; combined P = 2.7 × 10−11; odds ratio 1.26, 95% confidence interval (CI) 1.18–1.35) and the second within LIN28B (rs17065417; combined P = 1.2 × 10−8; odds ratio 1.38, 95% CI 1.23–1.54). Expression of LIN28B and let-7 miRNA correlated with rs17065417 genotype in neuroblastoma cell lines, and we observed significant growth inhibition upon depletion of LIN28B, specifically in neuroblastoma cells that were homozygous for the risk allele. Low HACE1 and high LIN28B expression in diagnostic primary neuroblastomas were associated with worse overall survival (P = 0.008 and 0.014, respectively). Taken together, these data show that common variants in HACE1 and LIN28B influence neuroblastoma susceptibility and indicate that both genes likely have a role in disease progression.