Pediatric Rhabdomyosarcoma

Abstract

Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood, and despite clinical advances, subsets of these patients continue to suffer high levels of morbidity and mortality associated with their disease. Recent genetic and molecular characterization of these tumors using sophisticated genomics techniques, including next-generation sequencing experiments, has revealed multiple areas that can be exploited for new molecularly targeted therapies for this disease.

FIG. 1

Whole-genome sequencing has revealed that rhabdomyosarcoma tumors can be classified into 2 distinct genotypes characterized by the absence (a) or presence (b) of a PAX gene rearrangement. CIRCOS plots from representative tumors are presented (from the outside circle in). Mutated genes: missense mutations (black), non-sense mutations and insertions/deletions (red); genomic location: genome-wide copy number alterations (gray), lesser allele frequency (green), loss of heterozygosity (dotted track), density of heterozygous single nucleotide polymorphisms (SNPs) (orange), homozygous SNPs (blue); intrachromasomal rearrangements (inner circle, gray) and interchromosomal rearrangements (inner circle, red). Adapted from Shern et al.

FIG. 2

A summary of the genomic alterations frequently occurring in primary rhabdomyosarcoma shows 2 distinct genotypes defined by the presence or absence of a PAX gene fusion and recurrent mutation of RAS pathway genes in fusion-negative tumors. Adapted from Shern et al.

FIG. 3

The interaction of PAX3-FOXO1 with genomic locations. As determined by chromatin precipitation, the PAX3-FOXO1 fusion gene is typically associated with enhancer regions of the genome. Presented here are the fusion gene binding sites in the MYOD1 enhancer region (top panel) and its relationship to other epigenetic and transcriptional marks (bottom panel).

FIG. 4

Summary of the potential therapeutic options outlined in this review. Adapted from Shern et al.