Abstract 4879: Genomic and epigenomic profiling of high-stage neuroblastoma

Abstract

Abstract Neuroblastoma (NB) is the most common pediatric extracranial solid tumor with a wide range of clinical phenotypes from spontaneous regression to highly resistant to chemotherapy. Despite intense multi-modal therapy, NB remains the second most common cause of cancer deaths among children. MYCN amplification is the most prominent poor prognosis factor for NB, however, certain subgroup of high stage tumor without MYCN amplification also shows low survival rate in terms of long-term follow-up (10 years survival rate was 51%, n=161). To elucidate the molecular basis of malignant subtype of NB, integrated genomic and epigenomic analyses were performed. Array CGH of 537 tumors indicated that genomic subgroups of 17q gain, with 1p loss and/or 11q loss, exhibited aggressive characteristics even without MYCN amplification. Whole exome sequencing of 92 high stage, MYCN-non-amplified primary tumors (SureSelect XT Human All Exon V4, mean depth CDS:138, x20 coverage:96%) identified 1,735 non-silent somatic mutations, among which 53 were significant mutations observed more than once in the sample set. Aggressive tumors (died of disease, n=48) had several notable features, with mutations in chromatin remodeling/modulating genes (27%, cf. ATRX), in DNA-damage response (30%), in TP53 (28%) and RB (22%)-related gene networks, as well as with high TERT expression (38%). By hierarchical clustering of methylome signature (Infinium HumanMethylation450 BeadChip), the 92 tumors were subdivided into four clusters. Unfavorable cluster-2 and -4 exhibited hyper-methylation phenotypes in CpG islands and the former was enriched by MYCN-amplified tumors. These two clusters (53%) showed strong correlation with patient prognosis (p=0.0055). Thus, these prognosis-related genomic features could be useful markers for risk classification and help understanding molecular mechanism for aggressive phenotypes of MYCN-non-amplified NBs. Citation Format: Miki Ohira, Yasutoshi Tatsumi, Yohko Nakamura, Kenji Tatsuno, Shuichi Tsutsumi, Shogo Yamamoto, Genta Nagae, Claire Renard-Guillet, Ryuichi Sugino, Hiroki Nagase, Takehiko Kamijo, Hiroyuki Aburatani, Akira Nakagawara. Genomic and epigenomic profiling of high-stage neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4879. doi:10.1158/1538-7445.AM2017-4879