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Neuroblastoma is a cancer of the developing sympathetic nervous system that most commonly presents in young children and accounts for approximately 12% of pediatric oncology deaths. Here, we report on a genome-wide association study (GWAS) in a discovery cohort or 2,101 cases and 4,202 controls of European ancestry. We identify two new association signals at 3q25 and 4p16 that replicated robustly in multiple independent cohorts comprising 1,163 cases and 4,396 controls (3q25: rs6441201 combined P = 1.2x10 -11 , Odds Ratio 1.23, 95% CI:1.16–1.31; 4p16: rs3796727 combined P = 1.26x10 -12 , Odds Ratio 1.30, 95% CI: 1.21–1.40). The 4p16 signal maps within the carboxypeptidase Z ( CPZ ) gene. The 3q25 signal resides within the arginine/serine-rich coiled-coil 1 ( RSRC1 ) gene and upstream of the myeloid leukemia factor 1 ( MLF1 ) gene. Increased expression of  MLF1  was observed in neuroblastoma cells homozygous for the rs6441201 risk allele (P = 0.02), and significant growth inhibition was observed upon depletion of  MLF1  (P < 0.0001) in neuroblastoma cells. Taken together, we show that common DNA variants within  CPZ  at 4p16 and upstream of  MLF1  at 3q25 influence neuroblastoma susceptibility and  MLF1  likely plays an important role in neuroblastoma tumorigenesis.

Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma