Genomic analysis–integrated whole-exome sequencing of neuroblastomas identifies genetic mutations in axon guidance pathway

// Yuanyuan Li 1, 2, * , Miki Ohira 3, 4, * , Yong Zhou 5, * , Teng Xiong 5, * , Wen Luo 5 , Chao Yang 5 , Xiangchun Li 5 , Zhibo Gao 5 , Rui Zhou 5 , Yohko Nakamura 2 , Takehiko Kamijo 4 , Yasuhiko Kaneko 4 , Takeshi Taketani 6 , Junichi Ueyama 7 , Tatsuro Tajiri 8 , Hongyan Zhang 5 , Jian Wang 5, 9 , Huanming Yang 5, 9 , Ye Yin 5 and Akira Nakagawara 1, 2 1 Life Science Research Institute, Saga Medical Center Koseikan, Saga, Japan 2 Division of Biochemistry and Innovative Cancer Therapy, Chiba Cancer Center Research Institute, Chiba, Japan 3 Division of Cancer Genomics, Chiba Cancer Center Research Institute, Chiba, Japan 4 Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan 5 BGI-Shenzhen, Shenzhen, China 6 Department of Pediatrics, Shimane University School of Medicine, Shimane, Japan 7 Division of Pediatrics and Perinatology, Tottori University School of Medicine, Tottori, Japan 8 Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan 9 James D. Watson Institute of Genome Science, Hangzhou, China * These authors have contributed equally to this work Correspondence to: Akira Nakagawara, email: nakagawara-a@koseikan.jp Ye Yin, email: yinye@genomics.cn Keywords: whole-exome sequencing, array CGH, neuroblastoma, familial neuroblastoma, genomic diversity Received: February 07, 2017     Accepted: April 27, 2017     Published: May 23, 2017 ABSTRACT 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.