Gene fusions in soft tissue tumors: Recurrent and overlapping pathogenetic themes

Abstract

Gene fusions have been described in approximately one-third of soft tissue tumors (STT); of the 142 different fusions that have been reported, more than half are recurrent in the same histologic subtype. These gene fusions constitute pivotal driver mutations, and detailed studies of their cellular effects have provided important knowledge about pathogenetic mechanisms in STT. Furthermore, most fusions are strongly associated with a particular histotype, serving as ideal molecular diagnostic markers. In recent years, it has also become apparent that some chimeric proteins, directly or indirectly, constitute excellent treatment targets, making the detection of gene fusions in STT ever more important. Indeed, pharmacological treatment of STT displaying fusions that activate protein kinases, such as ALK and ROS1, or growth factors, such as PDGFB, is already in clinical use. However, the vast majority (52/78) of recurrent gene fusions create structurally altered and/or deregulated transcription factors, and a small but growing subset develops through rearranged chromatin regulators. The present review provides an overview of the spectrum of currently recognized gene fusions in STT, and, on the basis of the protein class involved, the mechanisms by which they exert their oncogenic effect are discussed.

Figure 1

Circos plot showing the chromosomal distribution of genes involved in recurrent and non-recurrent gene fusiosn in soft tissue tumors. Black lines 5 fusions involving genes on different chromosomes; green lines 5 fusions arising through intra-chromosomal rearrangements; red lines 5 fusion of genes located in the same chromosome band. The numbers outside the circos plot refer to the number of different gene fusions per chromosome band. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 2

Network of gene fusions in soft tissue tumors. Some genes—ALK, EWSR1, FUS, HMGA2, NCOA2, and PLAG1 (indicated in red)—are promiscuous in the sense that they recombine with more than five different partners, leading to the formation of interconnected networks. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]