The genetic landscape of high-risk neuroblastoma

Abstract

Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%1. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 cases using a combination of whole exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per megabase (0.48 non-silent), and remarkably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, an additional 7.1% had focal deletions), MYCN (1.7%, a recurrent p.Pro44Leu alteration), and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1, and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies reliant upon frequently altered oncogenic drivers.

Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone

“…Somatic alterations of the ATRX gene were reported to occur in 10% to 22% of stage 4 neuroblastoma tumors. Seventy percent of these alterations, which are exclusively present in patients !18 months with non-MNA tumors, were found in the form of deletions within this gene (6,(9)(10)(11)(12). This aberration is proposed to define a subgroup of high-risk neuroblastomas resulting in elongation of telomeres by alternative lengthening of telomeres, ALT (10,12).…”

“…Overall, low-risk neuroblastomas mostly have whole chromosomal gains without structural aberrations. High-risk neuroblastomas, for example, mostly stage 4, on the contrary, present with different structural aberrations in the form of gains or losses of large chromosomal segments, referred to as segmental chromosomal aberrations (SCAs), MYCN amplification (MNA), and/or mutations as well as copy-number alterations affecting certain genes or parts thereof (5)(6)(7)(8)(9)(10)(11)(12)(13). Whether genetic markers might help to identify the relapse-seeding clone and to categorize stage 4 patients into different prognostic subgroups is still a matter of debate.…”

Problems, challenges and promises: perspectives on precision medicine

“…In a recent example in our own work, we globally profiled a panel of heterogeneous neuroblastoma cell lines. Neuroblastoma is a cancer which is notorious for its heterogenous outcomes and underlying genetic and epigenetic drivers, with a dearth of recurrent somatic mutations across patients [33]. Yet our network based analysis revealed that, rather than massively heterogeneous alterations in the regulators of each MYCN amplified cell line, there was a remarkable consistency in both the top regulators and their extent of activation/inhibition (under review).…”

Systematic identification of cancer-specific MHC-binding peptides with RAVEN

“…6,7 This restricted expression pattern increases the likelihood of circulating lymphocytes directed against immunogenic peptides encoded by these CSGs, 7 which can be exploited clinically. In neuroblastoma and Ewing sarcoma, which are aggressive and oligo-mutated pediatric cancers, 8,9 adoptive T cell therapy targeting CSGs has been successfully applied in humanized mouse models 10–13 and patients. 14 Screening for additional CSGs could be enabled by comprehensive and already available transcriptome datasets of cancer and normal tissues, 15 However, due to the lack of specific algorithms and user-friendly tools, the identification of CSGs and derivative peptides with high affinity to MHCs continues to be laborious and slow.…”