Osteosarcoma, an aggressive type of bone cancer, commonly affects children and young adults. Despite being rare, it impacts young people and their families as treatment can require surgery or amputation.
This cancer could potentially spread to other organs, most importantly lungs. However, due to its genomic complexity, it is 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.
A new study, which analyzed the largest collection of whole-genome data from osteosarcoma patients, has solved the mystery of what drives the genomic rearrangements causing osteosarcoma tumors’ aggressive development and evolution. Researchers specifically identified a new mutation mechanism called loss-translocation-amplification (LTA) chromothripsis.
This mechanism is identified to be present in approximately 50% of high-grade osteosarcoma cases.
This study was conducted in collaboration between researchers at EMBL’s European Bioinformatics Institute (EMBL-EBI), University College London (UCL), the Royal National Orthopaedic Hospital, and Genomics England’s R&D laboratory.
This discovery sheds light on the unique biology that makes this tumor type aggressive and explains the high levels of genomic instability in osteosarcoma cancer cells. Additionally, the study identifies a prognostic biomarker, a biological characteristic of cancer cells, which could help predict the patient’s outcome and anticipate the likely course of the disease.
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 understood how chromosomes break and rearrange and how this impacts osteosarcoma disease progression.”
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This study examined different parts of osteosarcoma tumors using a method called long-read sequencing, which was key to discovering the LTA chromothripsis mechanism. It found that in cancer cells, the chromosomes keep developing more abnormalities as the cancer grows, helping the tumors avoid treatment.
The researchers also examined genome data from over 5,300 tumors from various types of cancer. They found that many complex chromosomal abnormalities in different cancers are caused by highly unstable chromosomes affected by chromothripsis. This finding is important for treating various cancers, suggesting that the instability seen in osteosarcoma is also relevant to other cancers.
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, said, “Our additional analysis of different tumor types has shown that chromosomes affected by complex genomic rearrangements are also common and unstable in other cancers. This greatly impacts our overall understanding of cancer development, highlighting the importance of investing in studies that explore these mechanisms.”
This research used data from the 100,000 Genomes Project, which Genomics England and NHS England led. They sequenced whole genomes from NHS patients with rare conditions or cancer. By examining genomic data from many osteosarcoma patients, researchers found that LTA chromothripsis occurs in about 50% of pediatric and adult high-grade osteosarcomas.
However, it rarely happens in other types of cancer, highlighting the need for large-scale analysis of rare cancers to identify the specific mutations that drive their development.
Greg Elgar, Director of Sequencing R&D at Genomics England, stated that these discoveries greatly improve our understanding of what drives the progression of this aggressive bone cancer and how it may develop in patients.
He noted that these new insights could improve treatment options and outcomes through more targeted care. The research shows the potential of combining efforts from academia, clinical practice, and the NHS to achieve significant advancements.
Predicting the likely course of osteosarcoma (a type of bone cancer) is challenging. This study introduced a new way to predict outcomes: a biomarker called loss of heterozygosity (LOH). LOH happens when one copy of a genomic region is lost. In osteosarcoma, a high level of LOH indicates a lower chance of survival.
Adrienne Flanagan, a Professor at UCL and Consultant Histopathologist at RNOH, explained, “This biomarker could help identify patients who may not benefit from certain treatments that can have unpleasant and difficult side effects. This allows for more personalized treatments and helps avoid unnecessary toxic therapies.”
Journal Reference:
- Jose Espejo Valle-Inclan, Solange De Noon et al. Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution. Cell. DOI: 10.1016/j.cell.2024.12.005
Source: Tech Explorist
