TY - JOUR
T1 - Genomic analysis-integrated whole-exome sequencing of neuroblastomas identifies genetic mutations in axon guidance pathway
AU - Li, Yuanyuan
AU - Ohira, Miki
AU - Zhou, Yong
AU - Xiong, Teng
AU - Luo, Wen
AU - Yang, Chao
AU - Li, Xiangchun
AU - Gao, Zhibo
AU - Zhou, Rui
AU - Nakamura, Yohko
AU - Kamijo, Takehiko
AU - Kaneko, Yasuhiko
AU - Taketani, Takeshi
AU - Ueyama, Junichi
AU - Tajiri, Tatsuro
AU - Zhang, Hongyan
AU - Wang, Jian
AU - Yang, Huanming
AU - Yin, Ye
AU - Nakagawara, Akira
N1 - Funding Information:
This work was supported in part by a Grant from Takeda Science Foundation (AN, MO), the National Cancer Center Research and Development Fund (AN), Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT) (AN, MO, YN), the Research Program on Pediatric Solid Tumors from the Japan Agency for Medical Research and Development (AN) and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (JSPS KAKENHI Grant Number: 24249061 (AN), 23591562 (MO) and 26461603 (MO)).
Publisher Copyright:
© Li et al.
PY - 2017
Y1 - 2017
N2 - Neuroblastoma (NB) is a childhood solid malignant tumor originating from precursor cells of the peripheral nervous system. We have previously established a risk classification system based on DNA copy number profiles. To further explore the pathogenesis of NBs in distinct risk groups, we performed whole-exome sequencing analysis of 57 primary and 7 recurrent/metastatic tumors with unique chromosomal aberration profiles as categorized by our genomic sub-grouping system. Overall, a low frequency of somatic mutations was found. Besides ALK (4/64, 6.3%), SEMA6C, SLIT1 and NRAS, genes involved in the axon guidance pathway, were identified as recurrently mutated in 6 of 64 tumors (9.4%). Pathway enrichment analysis revealed enrichment of 25 mutated genes in the mitogen-activated protein kinase (MAPK) pathway, 13 genes in the Wnt pathway, and 12 genes in the axon guidance pathway. Genomic analyses demonstrated that primary and matched recurrent or metastatic tumors obtained from sporadic and monozygotic twin NBs were clonally related with variable extents of genetic heterogeneity. Monozygotic twin NBs displayed different evolutionary trajectories. These results indicate the involvement of the axon guidance, MAPK and Wnt pathways in NB and demonstrate genomic diversity with NB progression.
AB - Neuroblastoma (NB) is a childhood solid malignant tumor originating from precursor cells of the peripheral nervous system. We have previously established a risk classification system based on DNA copy number profiles. To further explore the pathogenesis of NBs in distinct risk groups, we performed whole-exome sequencing analysis of 57 primary and 7 recurrent/metastatic tumors with unique chromosomal aberration profiles as categorized by our genomic sub-grouping system. Overall, a low frequency of somatic mutations was found. Besides ALK (4/64, 6.3%), SEMA6C, SLIT1 and NRAS, genes involved in the axon guidance pathway, were identified as recurrently mutated in 6 of 64 tumors (9.4%). Pathway enrichment analysis revealed enrichment of 25 mutated genes in the mitogen-activated protein kinase (MAPK) pathway, 13 genes in the Wnt pathway, and 12 genes in the axon guidance pathway. Genomic analyses demonstrated that primary and matched recurrent or metastatic tumors obtained from sporadic and monozygotic twin NBs were clonally related with variable extents of genetic heterogeneity. Monozygotic twin NBs displayed different evolutionary trajectories. These results indicate the involvement of the axon guidance, MAPK and Wnt pathways in NB and demonstrate genomic diversity with NB progression.
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U2 - 10.18632/oncotarget.18079
DO - 10.18632/oncotarget.18079
M3 - Article
AN - SCOPUS:85029055441
VL - 8
SP - 56684
EP - 56697
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 34
ER -