Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma

Abstract

Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma, we performed whole-genome sequencing (6 cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases) and targeted analyses of specific genomic loci (40 cases) using massively parallel sequencing. On average, each tumor had 19 somatic alterations in coding genes (range of 3-70). Among genes not previously known to be involved in neuroblastoma, chromosomal deletions and sequence alterations of the chromatin-remodeling genes ARID1A and ARID1B were identified in 8 of 71 tumors (11%) and were associated with early treatment failure and decreased survival. Using tumor-specific structural alterations, we developed an approach to identify rearranged DNA fragments in sera, providing personalized biomarkers for minimal residual disease detection and monitoring. These results highlight the dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of patients with neuroblastoma.

Figure 1. Number and type of somatic alterations detected in each neuroblastoma case

The vertical axis includes non-synonymous single base substitutions, insertions, deletions, and splice site changes (NS Mutations), homozygous deletions and amplifications affecting protein encoding genes, and rearrangements with at least one breakpoint within the coding region of a gene. The inset shows the mutation spectra of somatic non-silent single nucleotide mutations in 16 cases of neuroblastoma. Data on rearrangements and copy number changes were not available for starred samples.

Figure 2. Genomic alterations in ARID1A and ARID1B

The schematic represents the ARID1B and ARID1A proteins with the predicted effects of observed intragenic deletions and point mutations.

Figure 3. Overall survival according to ARID1 status

The hazard ratio for death among patients with wildtype ARID1B/A (n=48), as compared to those with mutant ARID1B/A (n = 7) was 4.49 (95% confidence interval, CI 1.24–16.33; P=0.0226, log-rank test). The median survival was 1689 days for patients with wildtype ARID1B/A compared to 386 days for patients with mutated ARID1B/A. An analysis that also included hemizygous deletions of the entire coding region of ARIDB further increased the significance of the survival difference between patients with mutant and wildtype ARID1B/A (hazard ratio, HR 6.41; 95% confidence interval, CI 1.93–21.25; P=0.0024, log-rank test).