Our study showed that chromosome 1 gene mutations occur frequently in 1p-intact neuroblastoma, but these do not consistently abrogate the function of bonafide tumor suppressors residing on 1p.. Mutational Analysis of 1p Tumor Suppressors in 1p-intact Neuroblastoma

Deletion of 1p is associated with poor prognosis in neuroblastoma, however selected 1p-intact patients still experience poor outcomes. Since mutations of 1p genes may produce deleterious functional effects, we characterized the clinical and mutational profile of 1p tumor suppressors and neuroblastoma candidate genes among 100 tumor-normal pairs from 1p-intact neuroblastoma patients. Chromosome 1 genes KIF1Bβ and CHD5 were most frequently mutated (2%) after ALK and ATRX (8%), and BARD1 (3%). Chromosome 1 gene mutations were associated with other synchronous mutations and concurrent 11q deletion. In total, 24 of 38 variants were novel. Functional validation demonstrated novel variant KIF1Bβ I1355M as a gain-of-function mutation with increased expression and corresponding tumor suppressive activity, correlating with an indolent clinical course; CHD5 E43Q was a loss-of-function mutation with decreased expression, leading to increased long-term cell viability that corresponds with aggressive disease characteristics. Together, our study showed that chromosome 1 gene mutations occur frequently in 1p-intact neuroblastoma, but these do not consistently abrogate the function of bonafide tumor suppressors residing on 1p.