Identification of the genetic and clinical characteristics of neuroblastomas using genome-wide analysis

// Kumiko Uryu 1 , Riki Nishimura 1 , Keisuke Kataoka 2 , Yusuke Sato 2 , Atsuko Nakazawa 3 , Hiromichi Suzuki 2 , Kenichi Yoshida 2 , Masafumi Seki 1 , Mitsuteru Hiwatari 1, 4 , Tomoya Isobe 1 , Yuichi Shiraishi 5 , Kenichi Chiba 5 , Hiroko Tanaka 5 , Satoru Miyano 5 , Katsuyoshi Koh 6 , Ryoji Hanada 6 , Akira Oka 1 , Yasuhide Hayashi 7 , Miki Ohira 8 , Takehiko Kamijo 8 , Hiroki Nagase 9 , Tetsuya Takimoto 10 , Tatsuro Tajiri 11 , Akira Nakagawara 11, 12 , Seishi Ogawa 2 and Junko Takita 1 1 Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan2 Department of Pathology and Tumor Biology, Graduate School of Medicine, University of Kyoto, Kyoto, Japan3 Department of Pathology, National Center for Child Health and Development, Tokyo, Japan4 Cell Therapy and Transplantation Medicine, The University of Tokyo, Japan5 Laboratory of DNA Information Analysis, Human Genome Centre, Institute of Medical Science, The University of Tokyo, Tokyo, Japan6 Saitama Children’s Medical Center, Saitama, Japan7 Gunma Red Cross Blood Center, Japanese Red Cross Society, Gunma, Japan8 Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan9 Laboratory of Cancer Genetics, Chiba CancerResearch Institute, Chiba, Japan10 National Center for Child Health and Development, Tokyo, Japan11 Japan NeuroblastomaStudy Group 12 Saga Medical Center Koseikan, Saga, JapanCorrespondence to: Junko Takita, email: jtakita-tky@umin.ac.jp Keywords: copy number variants; target amplicon deep sequencing; ALK; ALK immunohistochemistry staining; Japan neuroblastomastudy group (JNBSG) Received: July 10, 2017 Accepted: October 28, 2017 Published: November 18, 2017 ABSTRACT To provide better insight into the genetic signatures of neuroblastomas, we analyzed 500 neuroblastomas(included specimens from JNBSG) using targeted- deep sequencingfor 10 neuroblastoma-related genes and SNP arraysanalysis. ALK expression was evaluated using immunohistochemical analysis in 259 samples. Based on genetic alterations, the following 6 subgroups were identified: groups A ( ALK abnormalities), B (other gene mutations), C ( MYCN amplification), D (11q lossof heterozygosity[LOH]), E (at least 1 copy number variants), and F (no genetic changes). Groups A to D showed advanced disease and poor prognosis, whereas groups E and F showed excellent prognosis. Intriguingly, in group A, MYCN amplification was not a significant prognostic marker, while high ALK expression was a relevant indicator for prognosis ( P = 0.033). Notably, the co-existence of MYCN amplification and 1p LOH, and the co-deletion of 3p and 11q were significant predictors of relapse ( P = 0.043 and P = 0.040). Additionally, 6q/8p LOH and 17q gain were promising indicators of survival in patients older than 5 years, and 1p, 4p, and 11q LOH potentially contributed to outcome prediction in the intermediate-risk group. Our genetic overview clarifies the clinical impact of genetic signatures and aids in the better understanding of genetic basis of neuroblastoma.