Poster Presentation Advances in Neuroblastoma Research Congress 2016

Loss of ATM function confers risk for advanced stage neuroblastoma but provides a therapeutic target for poly-ADP ribose polymerase inhibitors   (#303)

Masatoshi Takagi 1 , Misa Yoshida 2 , Yoshino Nemoto 1 , Hiroyuki Tamaichi 3 , Rika Tsuchida 1 , Masafumi Seki 2 , Kumiko Uryu 2 , Noriko Hoshino 2 , Rina Nishii 1 , Satoshi Miyamoto 1 , Masahiro Saito 3 , Toshiaki Shimizu 3 , Ryoji Hanada 4 , Hideo Kaneko 5 , Toshiyuki Fukao 6 , Takatoshi Koyama 1 , Yuichi Shiraishi 7 , Kenichi Chiba 7 , Hiroko Tanaka 7 , Satoru Miyano 7 , Yusuke Sato Sato 8 , Keisuke Kataoka 8 , Yusuke Okuno 8 9 , Kenichi Yoshida 8 , Tomohiro Morio 1 , Akira Oka 2 , Miki Ohira 10 11 , Yasuhide Hayashi 12 , Akira Nakagawara 11 13 , Seishi Ogawa 8 , Shuki Mizutani 1 , Junko Takita 2
  1. Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 1138519, Japan
  2. The University of Tokyo, Tokyo, Tokyo, Japan
  3. Juntendo University, School of Medicine, Tokyo, Japan
  4. Saitama Children’s Medical Center, Saitama, Japan
  5. Nagara Medical Center, Gifu, Japan
  6. Gifu University, Gifu, Japan
  7. Institute of Medical Science, The University of Tokyo, Tokyho, Japan
  8. Kyoto University, Kyoto, Japan
  9. Nagoya University, Nagoya, Japan
  10. Saitama Cancer Center Research Institute, Saitama, Japan
  11. Chiba Cancer Center, Chiba, Japan
  12. Gunma Red Cross Blood Center, Gumma, Japan
  13. Saga Medical Center, Koseikan, Saga, Japan

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Advanced NB is one of the most incurable childhood cancers. To improve NB treatment outcomes, risk classification, identification of molecular targets associated with prognosis and development of an optimized therapeutic approach are essential. Loss of 1p, 3p, and 11q are observed in advanced stage of NB, and are associated with an unfavorable prognosis. 11q deletion is observed in 30% of NB; these cases are known to harbor a MYCN single copy with distinct genetic subtypes. However, little is known about molecular target located in 11q. Here, we report the genomic alteration of ATM and other DNA damage response (DDR)-associated genes MRE11A, H2AFX and CHEK1 located in 11q as well as BRCA1, BARD1, CHEK2, MDM2 and TP53 in 45 NB-derived cell lines and 237 fresh tumor samples. ATM loss or imbalance was detected in 20% of NB, over 90% of which were stage 3 or 4. An additional 10% contained ATM mutations. Rare nucleotide variations in DDR-associated genes other than ATM were detected in 26% of samples, and were mutually exclusive. ATM-defective cells exhibited dysfunction in homologous recombination repair, suggesting the potential for synthetic lethality by PARP inhibition. Indeed, most NB-derived cell lines exhibited sensitivity to PARP inhibitor. PARP inhibitor sensitivity was also assessed using in vivo xenografts of ATM haploinsufficient SK-N-DZ cells into nude mice, wherein tumor cell growth was markedly attenuated in the group receiving PARP inhibitor treatment. Therefore, PARP inhibitors represent potential candidates for NB therapeutics. Administration of PARP inhibitors to a DDR-defective NB subgroup may contribute to increased survival, especially in advanced stage, poor-prognostic NB.

 

The authors declare no competing financial interests.