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

BMC Cancer

Tohari Sumanty¹  Byrrappa Venkatesh¹  Alvin Y. J. Ng¹  Eva Loh²  Huiyi Chen²  Sudhanshi Jain²  Eileen H. Q. Ng²  Wan Yi Seow²  Chik Hong Kuick²  Kenneth T. E. Chang²  Derrick W. Q. Lian²  Deborah Jasmine³  Zhi Xiong Chen³  Jia Ying Tan³  Amos H. P. Loh⁴  Shui Yen Soh⁴ 

[1] Comparative and Medical Genomics Laboratory, Institute of Molecular and Cell Biology, A*STAR;Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital;Neurodevelopment and Cancer Laboratory, NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore;VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital;

关键词: Neuroblastoma;    Chromosome 1;    Tumor suppressor;    Next-generation sequencing;    Synchronous Mutations;   

DOI  :  10.1186/s12885-022-09800-0

来源: DOAJ

【 摘 要 】

Abstract 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 chromosomal 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 significantly 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 neuroblastoma, but may not consistently abrogate the function of bonafide 1p tumor suppressors. These findings may augment the evolving model of compounding contributions of 1p gene aberrations toward tumor suppressor inactivation in neuroblastoma.

【 授权许可】

Unknown