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Home»News»Researchers uncover new mutational mechanism leading to cancer progression
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Researchers uncover new mutational mechanism leading to cancer progression

healthtostBy healthtostJanuary 15, 2025No Comments5 Mins Read
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Researchers Uncover New Mutational Mechanism Leading To Cancer Progression
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Osteosarcoma is a type of aggressive bone cancer that most often affects children and young adults between the ages of 10 and 20, during periods of rapid bone growth. Although rare, it has a significant impact on young people and their families as treatment may require surgery or amputation. Cancer also has the potential to spread to other organs, most commonly the lungs. Because osteosarcoma is so genomically complex, it has been difficult to identify which genetic mutations drive the disease. As a result, there has been little progress in treatment options over the past 40 years.

New research, published in the journal Cellsolves the mystery of what drives the genomic rearrangements that cause the aggressive growth and progression of osteosarcoma tumors. Analyzing the largest genome-wide data collection from patients with osteosarcoma, researchers identified a new mutation mechanism, called loss-translocation-gain (LTA) chromothripsis, which is present in about 50% of high-grade osteosarcoma cases.

This finding explains the unique biology that makes this tumor type so aggressive and the high levels of genomic instability seen in osteosarcoma cancer cells. The study also presents a prognostic biomarker—a biological characteristic of cancer cells that can help predict patient outcome—that can be used to predict 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 Orthopedic Hospital and the Genomics England Research and Development laboratory.

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

By studying the genetic abnormalities in different areas of each tumor and using new technologies that allow us to read large stretches of DNA, we were able to understand how chromosomes break and rearrange and how this affects osteosarcoma disease progression.”


Isidro Cortes-Ciriano, Group Leader, EMBL-EBI

Large-scale genomic analysis

This study analyzed multiple regions from each osteosarcoma tumor using long-read sequencing. This approach was crucial to identifying the mechanism of LTA chromophores and the discovery that chromosome rearrangements in cancer cells continue to acquire additional abnormalities as the cancer progresses. This helps tumors avoid treatment.

The researchers also analyzed whole-genome sequencing data from more than 5,300 tumors from various cancer types. Through this broader analysis, the researchers identified that complex chromosomal abnormalities in various cancers arise because chromosomes affected by chromosomal aberrations are highly unstable. This finding has important implications for the treatment of different types of cancer, suggesting that the genomic instability of complex chromosomes observed in osteosarcoma progression is also associated with other cancers.

“Our additional analysis of different tumor types showed 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 team leader at the Botton-Champalimaud Pancreatic Cancer Center. “This has a huge impact on our overall understanding of cancer development, underscoring the importance of investing in studies investigating these mechanisms.”

United efforts

This research used data from the 100,000 Genomes Project, a pioneering study led by Genomics England and NHS England, which sequences whole genomes from NHS patients affected by rare diseases or cancer. Analyzing genomic data from a large cohort of osteosarcoma patients, the researchers revealed a prevalence of LTA chromothripsis in approximately 50% of both pediatric and adult high-grade osteosarcoma. However, it is very rarely seen in other types of cancer, thus highlighting the need for large-scale analysis of rare cancers to identify the distinct mutations that underlie their development.

“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 can develop in a patient,” said Greg Elgar, Director of Sequencing R&D at Genomics England. “New insights could, over 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 efforts research and development in these three streams’.

Prognosis prediction

Predicting the prognosis – the likely course of the disease – for patients with osteosarcoma remains an important unmet need. As part of this study, the team also demonstrated a new 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 genome-wide LOH predicts a lower probability of survival.

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

Source:

European Laboratory of Molecular Biology

Journal Reference:

Valle-Inclan, EJ, et al. (2025). Ongoing chromothripsis supports osteosarcoma genome complexity and clonal evolution. Cell. doi.org/10.1016/j.cell.2024.12.005.

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