New insights into high grade serous ovarian cancer tumour evolution

A study led by researchers at the Institute of Genetics and Cancer has gained new insights into how high grade serous ovarian cancer tumours emerge and grow, opening new avenues to develop better treatments.

High grade serous ovarian cancer (HGSOC) is the most common type of ovarian cancer but there is little understanding of how these tumours evolve and few good treatment options for women who develop the disease.

Deciphering the structural variation across tumour genomes is crucial to determine the events driving tumour progression and better understand tumour adaptation and evolution.

The researchers assembled a large whole genome sequencing and gene expression dataset, including 324 of these tumours, in order to describe the mutational landscape driving HGSOC.

They found two divergent evolutionary trajectories, affecting patient survival and involving differing genomic environments. One involved homologous recombination repair deficiency (HRD), while the other was dominated by whole genome duplication (WGD) with frequent chromothripsis, breakage-fusion-bridges and extra-chromosomal DNA. 

These trajectories contributed to structural variation hotspots, containing candidate driver genes with significantly altered expression. While structural variation predominantly drives tumorigenesis, researchers found high mtDNA mutation loads associated with shorter patient survival. 

The study shows that a combination of mutations in the mitochondrial and nuclear genomes impact prognosis, suggesting strategies for patient stratification.

The study is published in the journal Nature Communications in an article entitled "Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer".

High grade serous ovarian cancer is a tumour type that shows extreme structural instability, resulting in chaotic new rearrangements of the entire human genome that are unique to each tumour. These rearrangements are challenging to study with current technologies, but we show that they produce discernible and recurring patterns across many patients. We also show that some recurrent rearrangements can create new vulnerabilities in the tumour that may be exploited by existing drugs. We hope that our study also provides a blueprint for other poorly studied cancers showing high structural diversity.

Dr Ailith Ewing Chancellor’s Fellow, MRC Human Genetics Unit
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