Introduction

Sarcomas include a large diverse group of tumors that likely are derived from cells of mesenchymal origin and can occur virtually in any organ site. Sarcomas can generally be characterized genetically as falling into two categories. One subgroup, comprising less than 50% of all sarcomas, are characterized by either recurrent chromosomal translocations (most commonly encoding fusion transcription factors) or point mutations of tyrosine kinase receptor genes (1). The second larger subgroup of sarcomas can be genetically classified as those with complex, aneuploid karyotypes associated with numerous chromosomal gains and losses. This subgroup of sarcomas often has abnormalities in the p53 or Rb pathways, or both (2,3). The aneuploid subgroup of sarcomas has recently been shown to have abnormally elongated telomeres compared to sarcomas characterized by specific, recurrent chromosomal translocations (4). A detailed discussion of each specific sarcoma subtype is beyond the scope of this chapter. We will instead present detailed information on four specific sarcomas, including Ewing's sarcomas (ES), dermatofibrosarcoma protuberans (DFSP), gastrointestinal stromal tumors (GISTs), and rhabdomyosarcomas (RMS). Each of these examples illustrates important aspects of sarcoma molecular genetics with direct relevance to diagnosis and targeted therapeutics.

Ewing's sarcoma

Ewing's sarcoma (ES) is a highly malignant disease of children and young adults which most commonly arises in bone, but can also be found in a wide variety of soft-tissue sites (5). Histology demonstrates small, round, blue cell morphology. Immunohistochemical staining is typically positive for CD99 and often positive for a number of neural markers such as S100, but these features are neither unique to ES nor do they definitively reveal the cell type of origin. Although many aspects of ES biology remain perplexing, understanding of this disease is now firmly anchored in the molecular genetics of the chromosome translocations found in these tumors. Progress in the molecular biology and classification of ES exemplifies progress in the molecular biology and classification of several other translocation-bearing sarcomas, where the characterization of these molecular events has led to a new generation of highly specific diagnostic tests.