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

Yusuke Sato,Katsuyoshi Koh,Yuichi Shiraishi,Tomoya Isobe,Mitsuteru Hiwatari,Hiroki Nagase,Kenichi Yoshida,Hiromichi Suzuki,Atsuko Nakazawa,Akira Nakagawara,Ryoji Hanada,Takehiko Kamijo,Tatsuro Tajiri,Akira Oka,Kumiko Uryu,Miki Ohira,Masafumi Seki,Seishi Ogawa,Hiroko Tanaka,Junko Takita,Tetsuya Takimoto,Kenichi Chiba,Yasuhide Hayashi,Keisuke Kataoka,Satoru Miyano,Riki Nishimura

doi:10.18632/oncotarget.22495

Abstract

To provide better insight into the genetic signatures of neuroblastomas, we analyzed 500 neuroblastomas (included specimens from JNBSG) using targeted-deep sequencing for 10 neuroblastoma-related genes and SNP arrays analysis. 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 loss of 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.

Highlights

RESULTSNeuroblastoma is the most common pediatric extracranial solid tumor and accounts for approximately 15% of all pediatric cancer-related deaths [1]
The present comprehensive genetic analysis revealed the whole features of the copy number variations (CNVs) and mutation spectrum of major driver genes in a large series of neuroblastoma specimens
Neuroblastoma patients can be divided into 6 molecular subgroups, which displayed different clinical characteristics, confirming the genetic diversity of neuroblastomas

Summary

RESULTS

Neuroblastoma is the most common pediatric extracranial solid tumor and accounts for approximately 15% of all pediatric cancer-related deaths [1]. There was high concordance between MYCN amplification and 1p LOH in group A1, whereas a variety of copy number changes, including 7q or whole chromosome 7 gain and whole chromosome 17 gain were significantly gathered in group A2 compared to A1 (7q or whole 7 gain: Pc < 0.0001 and whole chromosome 17 gain: Pc = 0.0016) (Supplementary Table 2), suggesting that co-operating events in subgroup A tumors exhibited a highly genetic heterogeneity. ATRX alterations and 1q gain were dominantly detected in the relapsed group, but the significant genetic differences between relapsed and refractory groups in our cohort were not observed (Figure 7 and Supplementary Table 7). The 101 cases with a high ALK score were characterized by specific molecular (MYCN amplification; 1p, 3p, and 11q LOH; and 1q, 2p, and 17q gains), clinical (stage 4, relapsed disease, and primary adrenal site), and pathological parameters (INPC; unfavorable histology) (Supplementary Table 10).

DISCUSSION

MATERIALS AND METHODS

Findings

CONFLICTS OF INTEREST