Mutations of 1p genes do not consistently abrogate tumor suppressor functions in 1p-intact neuroblastoma. Mutations of 1p genes do not consistently abrogate tumor suppressor functions in 1p-intact neuroblastoma

Background: 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 mimic the deleterious effects of chromo- somal loss, we studied the incidence, spectrum and effects of mutational variants in 1p-intact neuroblastoma. Methods: We characterized the 1p status of 325 neuroblastoma patients, and correlated the mutational status of 1p tumor suppressors and neuroblastoma candidate genes with survival outcomes among 100 1p-intact cases, then performed functional validation of selected novel variants of 1p36 genes identified from our patient cohort. Results: Among patients with adverse disease characteristics, those who additionally had 1p deletion had signifi- cantly worse overall survival. Among 100 tumor-normal pairs sequenced, somatic mutations of 1p tumor suppressors KIF1Bβ and CHD5 were most frequent (2%) after ALK and ATRX (8%), and BARD1 (3%). Mutations of neuroblastoma candidate genes were associated with other synchronous mutations and concurrent 11q deletion (P=0.045). In total, 24 of 38 variants identified were novel and predicted to be deleterious or pathogenic. Functional validation identified novel KIF1Bβ I1355M variant as a gain-of-function mutation with increased expression and tumor suppressive activity, correlating with indolent clinical behavior; another novel variant CHD5 E43Q was a loss-of-function mutation with decreased expression and increased long-term cell viability, corresponding with aggressive disease characteristics. Conclusions: Our study showed that chromosome 1 gene mutations occurred frequently in 1p-intact neuroblas- toma, but may not consistently abrogate the function of bonafide 1p tumor suppressors. These findings may aug- ment the evolving model of compounding contributions of 1p gene aberrations toward tumor suppressor inactiva- tion in neuroblastoma.