Researchers discover a major driver of osteosarcoma

A major driver of the bone cancer osteosarcoma has been discovered by researchers from UCL, EMBL EBI and the Royal National Orthopaedic Hospital, providing insights that could help to predict cancer severity and how patients will respond to treatment.

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 disease also has the potential to spread to other organs, most commonly the lungs.

The genomic complexity of osteosarcoma has made it challenging to identify the specific genetic mutations that drive the disease, with little progress in treatment options over the past 40 years.

The new study, published in Cell, solves the mystery of what drives the genetic rearrangements that are responsible for the aggressive development and evolution of osteosarcoma tumors.

The researchers analysed the largest available collection of whole-genome data from osteosarcoma patients and identified a new mutation mechanism called loss-translocation-amplification (LTA) chromothripsis, which is present in approximately 50% of high-grade osteosarcoma cases.

The findings explain the unique biology that causes this tumor type to be so aggressive and the high levels of genomic instability observed in osteosarcoma cancer cells.

The team also made advances in predicting the likely course of osteosarcoma, which is a major unmet need in oncology.

They found that a biological characteristic called loss of heterozygosity (LOH), which occurs when one copy of a genomic region is lost, was predictive of patient outcomes in osteosarcoma. A high degree of LOH across the genome predicts a lower survival probability.

Our results have the potential of changing the clinical management of osteosarcoma by selecting those patients that are more likely to benefit from chemotherapy. These drugs have very unpleasant side effects and can be poorly tolerated by patients.

It also means that we may be able to better diagnose low-grade cases where surgery alone will likely be sufficient to remove the cancer, sparing patients unnecessary chemotherapy.

Overall, this research should lead to provision of more tailored treatments and help to spare them from unnecessary side effects of toxic therapies."

Professor Adrienne Flanagan, co-senior author of the study from UCL Cancer Institute and a Consultant Histopathologist at RNO

Dr. Solange De Noon, co-first author of the study from UCL Cancer Institute and EMBL-EBI, said: "Our work to uncover a key biological mechanism that drives osteosarcoma and gain insight into how a patient's disease is likely to behave represents a significant achievement for osteosarcoma research, especially after four decades where diagnosis and treatment haven't seen significant progress.

"The next step will be to explore the potential of a test for loss of heterozygosity that can be used in the clinic, with the aim of giving doctors reliable information to help personalise each patient's care based on the specific characteristics of their cancer."

The study analyzed multiple regions from each osteosarcoma tumor using long-read genome 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 tumors evade treatment. 

The researchers also analysed whole-genome sequencing data from over 5,300 tumors 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.

Isidro Cortes-Ciriano, Group Leader at EMBL-EBI and co-senior author of the study, said: "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.

"By studying the genetic abnormalities in different regions of each tumor 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."

The 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.

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