Poster Presentation Advances in Neuroblastoma Research Congress 2016

Genetic characteristics of 494 neuroblastomas using genome-wide analysis combined with immunohistochemistry (#200)

Kumiko Uryu 1 , Riki Nishimura 1 , Kenichi Yoshida 2 , Keisuke Kataoka 2 , Yuichi Shiraishi 3 , Kenichi Chiba 3 , Hiroko Tanaka 3 , Masafumi Seki 1 , Noriko Hoshino 4 , Mitsuteru Hiwatari 1 , Akira Oka 1 , Yasuhide Hayashi 5 , Atsuko Nakazawa 6 , Tetsuya Takimoto 7 , Tatsuro Tajiri 8 , Akira Nakagawara 8 , Satoru Miyano 3 , Seishi Ogawa 2 , Junko Takita 1
  1. Pediatrics, The University of Tokyo, Bunkyo-ku, TOKYO, Japan
  2. Pathology and Tumor Biology, Kyoto University, kyoto, KYOTO, Japan
  3. Human Genome Center, the institute of Medical Science, the University of Tokyo, Minato-ku, TOKYO, Japan
  4. Pediatrics surgery, The University of Tokyo, Bunkyo-ku, TOKYO, Japan
  5. Gunma　Red　Cross　Medical center, Maebashi, GUNMA, Japan
  6. Pathological diagnosis, Tokai university, Isehara, KANAGAWA, Japan
  7. National Center for Child Health and Development, Setagaya-ku, TOKYO, Japan
  8. Japan Neuroblastoma Study Group, Japan

Background

Neuroblastomas (NB) exhibits substantial heterogeneity; while some cases show spontaneous regression, the prognosis of advanced NBs is still poor in spite of recent developments in treatments. The best-characterized genetic alterations include amplification of MYCN, amplification/mutation of ALK, and losses of 1p and 11q. However, genotype/phenotype correlations in NB are still to be elucidated. Thus, to explore genetic basis of NB, we performed integrated genetic analysis combined with immunohistochemistry in a large series of NBs.  

 

Methods

We analyzed 494 NB samples, including stage 1, 2 (n = 106), stage 3 (n = 86), stage 4 (n = 282) and stage 4S (n = 20), using targeted deep sequencing for 10 NB related-genes (including ALK, ATRX, ARID1A/1B, PHOX2B, PTPN11). Copy number alterations were analyzed with SNP array. ALK Expression was also evaluated by immunohistochemistry in 241 NB samples obtained from Japan NB Study Group (JNBSG). 

 

Results

In this series, deep sequencing allows the detection of ALK (7.7% of cases), ARID1A /1B (7.3%), ATRX (4.9%). Based on genomic alterations, six major NB subgroups with different genetic signatures were identified; group A (ALK), group B (MYCN and 1p LOH), group C (other mutations), group D (11q LOH), group E (chromosome 17 gain), and group F (silent). Group D showed higher age of onset (median 44 months), whereas group E contained younger patients (median 7 months), mainly infants (p<0.0001). There was a significant association of high ALK expression and 2p gain, suggests that ALK copy number gain is one of the potential mechanisms of high ALK expression. Of note, among cases with high ALK expression, ALK mutation is a significant prognostic factor rather than MYCN amplification.

 

Conclusion                                

In this study, we disclosed genetic and pathological landscapes of a large NB series, which provide novel insights in to the pathogenesis of NB.