Advances in the translational genomics of neuroblastoma: From improving risk stratification and revealing novel biology to identifying actionable genomic alterations

Abstract

Neuroblastoma is an embryonal malignancy that commonly affects young children and is remarkably heterogenous in its malignant potential. Recently, the genetic basis of neuroblastoma has come into focus and not only has catalyzed a more comprehensive understanding of neuroblastoma tumorigenesis but also has revealed novel oncogenic vulnerabilities that are being therapeutically leveraged. Neuroblastoma is a model pediatric solid tumor in its use of recurrent genomic alterations, such as high-level MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog) amplification, for risk stratification. Given the relative paucity of recurrent, activating, somatic point mutations or gene fusions in primary neuroblastoma tumors studied at initial diagnosis, innovative treatment approaches beyond small molecules targeting mutated or dysregulated kinases will be required moving forward to achieve noticeable improvements in overall patient survival. However, the clonally acquired, oncogenic aberrations in relapsed neuroblastomas are currently being defined and may offer an opportunity to improve patient outcomes with molecularly targeted therapy directed toward aberrantly regulated pathways in relapsed disease. This review summarizes the current state of knowledge about neuroblastoma genetics and genomics, highlighting the improved prognostication and potential therapeutic opportunities that have arisen from recent advances in understanding germline predisposition, recurrent segmental chromosomal alterations, somatic point mutations and translocations, and clonal evolution in relapsed neuroblastoma.

Keywords: anaplastic lymphoma kinase (ALK); clonal evolution; genome-wide association studies; neuroblastoma; pediatric; v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN).

Figure 1. Rare and common genomic variants predispose to neuroblastoma

In addition to ALK and PHOX2B associated familial neuroblastoma, neuroblastoma can also arise in the setting of genetic syndromes with underlying RAS-MAPK pathway germline mutations such as NF1 in Neurofibromatosis type 1, PTPN11 in Noonan syndrome,^- and HRAS in Costello syndrome (left). TP53 mutations associated with Li Fraumeni syndrome, EZH2 mutations associated with Weaver syndrome and SDHB mutations in familial paraganglioma/pheochromocytoma (PGL/PCC) are also rarely associated with neuroblastoma genesis (left). Low frequency alleles in multiple DNA damage response genes (BARD1, CHEK2, PALB2, and TP53) with an intermediate effect size also contribute to neuroblastoma predisposition (middle) and more common alleles with a modest effect size discovered via a GWAS approach also collectively contribute to neuroblastoma genesis (right), and at times specifically to a high-risk (white) or low-risk (red) neuroblastoma phenotype.