Study unveils a new mechanism behind osteosarcoma and offers insights for predicting patient outcomes.
Osteosarcoma is an aggressive form of bone cancer primarily affecting children and young adults aged 10 to 20, coinciding with rapid periods of bone growth. While it is rare, it profoundly affects the lives of young patients and their families, often necessitating surgery or amputation. This cancer can also metastasize, usually targeting the lungs. Due to its complex genomic nature, pinpointing the genetic mutations that contribute to this disease has been difficult, resulting in minimal advancements in treatment options over the last four decades.
Recent research published in the journal Cell has uncovered the mechanisms behind the genomic changes that contribute to the aggressive nature and evolution of osteosarcoma tumors. By analyzing the largest dataset of whole-genome information from osteosarcoma patients, researchers discovered a novel mutation process known as loss-translocation-amplification (LTA) chromothripsis, found in roughly 50% of high-grade osteosarcoma instances.
This discovery sheds light on the unique biological characteristics that underpin the aggressiveness of these tumors, as well as the significant levels of genomic instability seen in osteosarcoma cells. The study introduces a prognostic biomarker—a biological indicator that may assist in predicting patient outcomes—helping to forecast the disease’s likely trajectory.
This research was a collaborative effort involving scientists from EMBL’s European Bioinformatics Institute (EMBL-EBI), University College London (UCL), the Royal National Orthopaedic Hospital, and Genomics England’s R&D laboratory.
“For years, we’ve known that osteosarcoma cells possess some of the most intricate genomes found in human cancers, yet we struggled to explain the underlying mechanisms,” explained Isidro Cortes-Ciriano, Group Leader at EMBL-EBI and co-senior author of the study. “By examining genetic anomalies in various regions of each tumor and utilizing advanced technologies for reading extensive DNA sequences, we have gained insight into how chromosomes break and rearrange, and how these processes affect the progression of osteosarcoma.”
Large-scale genomic analysis
This research employed long-read sequencing to analyze multiple regions from each osteosarcoma tumor, which proved essential in recognizing the LTA chromothripsis mechanism. It revealed that rearranged chromosomes in cancer cells continue to accumulate further abnormalities as the cancer advances, aiding in evasion of treatments.
The team also reviewed whole-genome sequencing data from over 5,300 tumors across various cancer types. This broader analysis indicated that complex chromosomal abnormalities emerge in multiple cancers due to the instability of chromosomes affected by chromothripsis. Such findings have crucial implications for treating various cancers, supporting the idea that the genomic instability observed in osteosarcoma could also be relevant to other forms of cancer.
“Our analysis of assorted tumor types revealed that chromosomes with complex genomic rearrangements are frequent and unstable in other cancers as well,” stated Jose Espejo Valle-Inclan, co-first author of the study and former postdoctoral fellow at EMBL-EBI, now a Group Leader at the Botton-Champalimaud Pancreatic Cancer Centre. “This significantly enhances our understanding of cancer development and underscores the need for further investment in research exploring these mechanisms.”
United efforts
This research utilized data from the 100,000 Genomes Project, a groundbreaking initiative led by Genomics England and NHS England, sequencing whole genomes of NHS patients with rare conditions or cancer. Through examining genomic data from a large group of osteosarcoma patients, the researchers highlighted that LTA chromothripsis is prevalent in about 50% of both pediatric and adult high-grade osteosarcomas, while being rarely seen in other cancers. This emphasizes the necessity for extensive analysis of rare cancers to identify their specific mutation patterns.
“These breakthroughs significantly enhance our understanding of what propels the progression of this aggressive bone cancer type and how it may evolve in patients,” remarked Greg Elgar, Director of Sequencing R&D at Genomics England. “These new findings could lead to improved treatment methods and patient outcomes over time through more personalized care. This research showcases the achievements possible when academic institutions, clinical settings, and the NHS collaborate to integrate research and development.”
Predicting prognosis
Accurately predicting the prognosis—the expected progression of the disease—for osteosarcoma patients remains a significant need. Within this study, the team also introduced a new prognostic biomarker for osteosarcoma: loss of heterozygosity (LOH). LOH occurs when one copy of a genomic region is missing. A high degree of LOH across the genome in osteosarcoma indicates a lower chance of survival.
“This biomarker could assist in identifying patients unlikely to benefit from treatments that can be quite harsh and difficult to endure,” said Adrienne Flanagan, Professor at UCL, Consultant Histopathologist at RNOH, and co-senior author of the study. “This is crucial for providing patients with more tailored therapeutic options and minimizing unnecessary adverse effects from toxic treatments.”
