Though adult cancers are associated with recurrent disease-specific somatic mutations driving disease progression and tumorigenesis, neuroblastoma is characterized by a lack of somatic mutations which hinders the development of therapies targeting mutated oncogenes. GWAS studies have revealed oncogenic vulnerabilities but these often have modest effect size and it is only through combinatorial effect that disease threshold is crossed.

Contrasting the results of GWAS, analysis of germline sequencing from the NCI-TARGET project is working to identify rare variants in the germline of neuroblastoma patients. Rare germline variants, those with minor allele frequency under 1% in the general population, may contribute to disease progression more significantly through a higher effect size than GWAS identified polymorphisms. For example, within TP53, SNPs strongly associated with neuroblastoma predisposition map to both the 3’ and 5’ UTRs of p53 and result in haploinsufficiency of normal protein (Stacey et al. 2011; Diskin et al. 2014), or in a truncated version which acts as an oncogene (Fujita et al. 2009), respectively.

Other rare variants have been discovered through whole genome and exome sequencing efforts. In addition to being heavily implicated in neuroblastoma predisposition, many variants are reported in the context of genetic syndromes such as Noonan, Li Fraumeni, Weaver, and familial paraganglioma/pheochromocytoma syndromes.

As with GWAS, we are extending these techniques to the study of other cancers, especially cranial malignancies. It is our hope that with these in-depth analyses, more promising treatments can be attained. Aiding our work on these are CHOP’s CBTTC, the NIH and Gabriella Miller Kids First, CHOP’s Center for Data-Driven Discovery in Biomedicine (D3B), and PedCBioPortal. Data sharing and collaboration will lead the way to new treatments and cures for kids.