First comprehensive molecular picture of ovarian carcinosarcoma

A study led by Edinburgh Cancer Centre scientists provides the first comprehensive molecular picture of ovarian carcinosarcoma (OCS), an uncommon form of ovarian cancer.

Ovarian carcinosarcoma (OCS) accounts for 2-4% of ovarian cancers and is a very aggressive cancer type with a median survival of only 12-24 months. Recurrence rate and mortality are high across all stages and new treatment strategies to improve survival are urgently needed. OCS is unique in that it is composed of two different components: one is epithelial (derived from cells that line anatomical structures), and the other is sarcomatous (derived from cells that form connective tissues). For a long time these cancers were thought to be related to a type of tumour called sarcoma (sarcomas are rare cancers that develop in the bones and soft tissues, including fat, muscles, blood vessels, nerves, deep skin tissues and fibrous tissues). However, in recent years, research (including studies from Edinburgh) demonstrated that OCS is related to common (epithelial) ovarian cancers, and that the sarcomatous population is formed from the carcinomatous population through a process known as epithelial to mesenchymal transition (EMT). The understanding of molecular similarities and differences between the two components is poor, but it might be of high importance in the context of molecular therapeutics. Therapies targeting molecular events shared between both compartments may be expected to demonstrate greater activity than those targeting molecules that are only altered in one of the two populations. Moreover, little is known about molecular events that may drive the carcinomatous component to undergo EMT and form the sarcomatous population. Consequently, there is an urgent need for studies in these areas.

Over the years, Edinburgh Cancer Researchers at the Institute of Genetics and Cancer have made significant contributions to our understanding of ovarian carcinosarcoma and helped define OCS as a distinct form of ovarian cancer. In a recent study they used sophisticated molecular biology techniques (including exome sequencing, RNA-sequencing and microRNA profiling) to provide detailed profiles of paired carcinomatous and sarcomatous components from several patients. Detailed analysis of the data demonstrated that copy number gain of the gene CCNE1 that encodes protein known as cyclin E1 (which helps regulate cell cycle progression) and loss of chromosome X represent frequent occurrences in OCS. Importantly, the study also suggested that increased activity of protein tyrosine-kinase Src (via gene copy number gain), increased expression of GNAS (a gene that provides instructions for making the stimulatory alpha subunit of a protein complex called a guanine nucleotide-binding protein or G-protein) and microRNA dysregulation, represent potential mechanisms driving sarcomatous compartment formation.      

The study was performed by a team consisting of Simon Herrington, Ailsa Oswald, Lorna Stillie, Ian Croy, Michael Churchman and Robert Hollis, all of whom work at the Nicola Murray Centre for Ovarian Cancer Research and at the CRUK Scotland Centre. Their work is published in the British Journal of Cancer in an article titled “Compartment-specific multiomic profiling identifies SRC and GNAS as candidate drivers of epithelial to mesenchymal transition in ovarian carcinosarcoma” (link below), with Dr Hollis serving as the corresponding author. The work was supported by funding from Tenovus Scotland, IGC Langmuir Talent Fellowship and PhD Studentships funded by Cancer Research UK and AstraZeneca. The microRNA profiling described in the article was funded and performed by HTG Molecular.

Our work provides comprehensive genomic, transcriptomic and microRNA profiling of paired carcinomatous and sarcomatous compartments in a series of ovarian carcinosarcoma cases. It dramatically increases our understanding of differences between carcinomatous and sarcomatous components in OCS and might guide some future therapeutic developments for this cancer type.