Researchers uncover new mutation mechanism driving cancer progression

Osteosarcoma is a type of aggressive bone cancer that most commonly affects children and young adults between the ages of 10 and 20, during times of rapid bone growth. Although rare, it has a significant impact on young people and their families as treatment can require surgery or amputation. The cancer also has the potential to spread to other organs, most commonly the lungs. Because osteosarcoma is so genomically complex, it has been challenging to identify what genetic mutations drive the disease. As a result, there has been little advancement in treatment options over the past 40 years. 

New research, published in the journal Cell, solves the mystery of what drives the genomic rearrangements causing the aggressive development and evolution of osteosarcoma tumours. By analysing the largest collection of whole-genome data from osteosarcoma patients, the researchers identified a new mutation mechanism, called loss-translocation-amplification (LTA) chromothripsis, which is present in approximately 50% of high-grade osteosarcoma cases. 

This finding explains the unique biology that makes this tumour type so aggressive and the high levels of genomic instability observed in osteosarcoma cancer cells. The study also presents a prognostic biomarker – a biological characteristic of cancer cells that can help predict patient outcome – that might be used to anticipate the likely course of the disease. 

This work is a collaboration between researchers at EMBL’s European Bioinformatics Institute (EMBL-EBI), University College London (UCL), the Royal National Orthopaedic Hospital, and the R&D laboratory of Genomics England. 

“We’ve known for years that osteosarcoma cells have some of the most complex genomes seen in human cancers, but we couldn’t explain the mechanisms behind this,” said Isidro Cortes-Ciriano, Group Leader at EMBL-EBI and co-senior author of the study.

By studying the genetic abnormalities in different regions of each tumour and using new technologies that let us read long stretches of DNA, we’ve been able to understand how chromosomes break and rearrange, and how this impacts osteosarcoma disease progression.”

Isidro Cortes-Ciriano, Group Leader, EMBL-EBI

Large-scale genomic analysis

This study analysed multiple regions from each osteosarcoma tumour using long-read sequencing. This approach was crucial in identifying the LTA chromothripsis mechanism and discovering that chromosomes rearranged in cancer cells continue to acquire additional abnormalities as cancer progresses. This helps tumours evade treatment. 

The researchers also analysed whole-genome sequencing data from over 5,300 tumours from diverse cancer types. Through this broader analysis, the researchers identified that very complex chromosomal abnormalities in various cancers arise because chromosomes affected by chromothripsis are highly unstable. This finding has significant implications for the treatment of diverse cancer types, suggesting that the genomic instability of complex chromosomes seen in osteosarcoma progression is also relevant to other cancers.

“Our additional analysis of different tumour types has shown that chromosomes affected by complex genomic rearrangements are also common and unstable in other cancers,” said Jose Espejo Valle-Inclan, co-first author of the study and former postdoctoral fellow at EMBL-EBI, currently Group Leader at the Botton-Champalimaud Pancreatic Cancer Centre. “This has a huge impact on our overall understanding of cancer development, highlighting the importance of investing in studies that explore these mechanisms.”

United efforts 

This research used data from the 100,000 Genomes Project, a pioneering study led by Genomics England and NHS England that sequenced whole genomes from NHS patients affected by rare conditions or cancer. By analysing genomic data from a large cohort of osteosarcoma patients, the researchers uncovered the prevalence of LTA chromothripsis in approximately 50% of both paediatric and adult high-grade osteosarcomas. However, it very rarely occurs in other cancer types, thus highlighting the need for large-scale analysis of rare cancers to identify the distinct mutations that underpin their evolution.

“These discoveries go a long way towards improving our understanding of what drives the progression of this aggressive type of bone cancer and how it may develop in a patient,” said Greg Elgar, Director of Sequencing R&D at Genomics England. “The new insights could, with time, lead to better treatment options and outcomes for patients through more targeted care. The research shows what can be achieved when academia, clinical practice, and the NHS work together and combine research and development efforts across these three streams.”

Predicting prognosis 

Predicting the prognosis – the likely course of the disease – for osteosarcoma patients remains a major unmet need. As part of this study, the team also presented a novel prognostic biomarker for osteosarcoma: loss of heterozygosity (LOH). LOH occurs when one copy of a genomic region is lost. In osteosarcoma, a high degree of LOH across the genome predicts a lower survival probability. 

“This biomarker could help us identify patients who are unlikely to benefit from treatment which can have very unpleasant effects and which patients find difficult to tolerate,” said Adrienne Flanagan, Professor at UCL, Consultant Histopathologist at RNOH, and co-senior author of the study. “This is invaluable for providing patients with more tailored treatments and help spare unnecessary effects of toxic therapies.”