Liposarcoma: molecular genetics and therapeutics

Abstract

Sarcomas are a group of heterogeneous tumours with varying genetic basis. Cytogenetic abnormalities range from distinct genomic rearrangements such as pathognomonic translocation events and common chromosomal amplification or loss, to more complex rearrangements involving multiple chromosomes. The different subtypes of liposarcoma are spread across this spectrum and constitute an interesting tumour type for molecular review. This paper will outline molecular pathogenesis of the three main subtypes of liposarcoma: well-differentiated/dedifferentiated, myxoid/round cell, and pleomorphic liposarcoma. Both the molecular basis and future avenues for therapeutic intervention will be discussed.

Figure 1

MDM2 binds to the transcriptional activation domain of p53, blocking transcription. MDM2 functions as a ubiquitin ligase, facilitating proteasomal degradation of p53. MDM2 releases p53 in response to cellular stress and p53 translocates to the nucleus where it acts as a transcription factor to enable growth arrest and apoptosis.

Figure 2

Cyclin dependent kinase CDK4 binds with cyclin D to form active complexes. This results in phosphorylation of Rb and dissociates pRb from the pRb-E2F complex. E2F binds DNA to upregulate transcription of genes required to progress to S phase.

Figure 3

The PI3K pathway is highly active in MLPS, and this is potentiated at least in part by overexpression, and/or activation through RTKs such as MET, RET and VEGFRs. Upon ligand binding, RTKs activate downstream activation of genes involved in multiple cell processes such as cell survival, proliferation, and angiogenesis. These signals are mediated through the PI3K/Akt pathway and also through RAS. PIK3CA and PTEN mutations and Akt activation have also been documented in MLPS.