Genome-wide analyses of sarcoma: implications for future treatment options.

Sarcomas are thought to originate from mes-enchymal tissue, and account for 1% of adult solid malignancies and over 20% of pediatric solid malignances. Nearly 11,000 people in the USA and 200,000 people in the world will be diagnosed with sarcomas each year [101]. When they metastasize, sarcomas typically have a very poor outcome. Unlike other types of tumors, the molecular basis and accompanying genomic changes in sarcoma are not well understood. This is due to the rarity of sarcoma and the difficulty in collecting enough fresh specimens for genomic ana lysis, which remains especially true for meta-static and relapsed lesions. Recurrent sarcomas have evolved the capacity to spread and resist therapy , although we still know very little about what drives their aggressiveness. As next-generation sequencing and other genome-wide technology becomes more readily available and affordable, we will begin to learn more about sarcomas and, thereby, increase our ability to identify candidate genes and pathways for therapeutic targeting. The molecular mechanisms for sarcoma genesis can be divided into three broad categories, as described by Taylor et al. in a recent review of sarcoma genomics and therapeutic targets [1]. These categories include: translocations that create fusion proteins leading to transcriptional dysregulation; somatic mutations; and DNA copy number changes. Advances in molecular technology have defined the genome-wide targets and transcriptional effects of sarcoma fusion proteins, starting initially with gene expression micro arrays and more recently with chromatin immuno-precipitation arrays and sequencing. Sarcomas can be categorized in several different ways. When creating a taxonomy for classification, soft tissue sarcomas can be divided by tissue of origin, by prognosis or even by specific driver alterations [1]. However, more typically, sarco-mas are divided into two categories: balanced translocation-associated sarcoma (BTAS; genome stable); and complex genotype–karyotype sar-coma (genome unstable) [2]. Each BTAS has its own recurring translocation. For instance, 85% of Ewing sarcomas will contain the t(11;22) (q24;q12) EWSR1/FLI1 trans location, and the remaining tumors will have EWSR1 bound to a different ETS protein (e.g., ERG, ETV1, ETV4 or FEV). Other BTASs include clear-cell sarcoma, desmoplastic small-round-cell tumor, myxoid chondrosarcoma, myxoid liposarcoma, alveolar rhabdomyosarcoma (ARMS), synovial sarcoma, dematrofibrosarcoma protuberans, congenital fibrosarcoma, inflammatory myo-fibroblastic tumor and alveolar soft-part sarcoma. The complex genotype–karyotype sarcoma category includes tumors with multiple genomic alterations such as osteosarcoma, undifferentiated pleomorphic sarcoma (formerly called malignant fibrous histiocytoma), embryonal rhabdomyo-sarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, angiosarcoma, fibrosarcoma (other than congenital), chondrosarcoma (other than …