Somatic structural variation (SV) in neuroblastoma
Neuroblastoma tumors harbor few recurrent mutations in protein coding genes compared to adult cancers. However, many neuroblastomas exhibit gains and losses of large segments of DNA. These copy number alterations have prognostic significance, and some are used clinically to assign treatment. Copy number alterations represent just one form of structural variation (SV). SVs can also include segments of DNA that are inverted or translocated to alter gene function and promote cancer. With support from the NIH/NCI, our laboratory is studying SVs in tumor and matched normal DNA of neuroblastoma patients using large-scale data from whole genome sequencing (WGS) and single nucleotide polymorphism (SNP) arrays coupled with experimental follow-up to assess biological relevance. In our germline SV studies of blood-derived normal DNA (see Genetic Predisposition), we have identified both common and rare CNVs as genetic risk factors for neuroblastoma. In tumor genomes, chromothripsis (“shattering” of DNA involving potentially thousands of clustered SVs in localized or confined genomic regions) occurs in 19% of high-risk cases. Specific genes are also targeted by SVs in neuroblastoma tumors. Somatic SVs upstream of the telomerase gene (TERT) are observed in 25% of high-risk cases; these SVs drive aberrant TERT expression via enhancer hijacking and influence telomere maintenance to promote cancer. Our work has also identified SHANK2 on chromosome 11 as a novel tumor suppressor gene whose normal function is to promote cellular differentiation; however, the gene is disrupted by recurrent SVs in neuroblastoma tumors. We are currently exploring long-read sequencing technologies to enhance SV detection and extending this work to additional patient cohorts and relapsed tumors.