Key Points:
- Scientists have created a roadmap of the genetic mutations present in the most common childhood cancer, acute lymphoblastic leukemia (ALL).
- The study identified many newly implicated genes that have not been reported in leukemia or cancer at all, and showed that they fall into several new cellular pathways.
- The findings bring physicians one step closer to personalized treatment for young cancer patients.
A 10+ year study by St. Jude scientists is the first to supply a comprehensive view of the genomics of all subtypes of acute lymphoblastic leukemia (ALL), the most common childhood cancer.
While most children with ALL are likely to survive, some do not respond well to treatment. Cancer researchers believe personalized medicine can change that—physicians could bring treatments to patients based on their genetics and likelihood of responding to specific therapies. But before bringing personalized therapies into the clinic, scientists need to map the different mutations that drive the development of leukemia across diverse subtypes.
Previous studies on ALL included hundreds of patient samples, or fewer. For this study, however, the St. Jude research team spent over a decade collecting pediatric samples—ending up with 2,574.
The samples were subjected to a combination of whole genome, whole exome or transcriptome sequencing. The researchers then compared the sequences to find patterns in the mutations. Overall, they identified 376 significantly mutated genes that potentially drive cancer development. Seventy of the genes have never been implicated in ALL. Some of the unexpected potential driver mutations are in genes involved with cellular processes such as ubiquitination, SUMOylation or non-coding cis-regulatory regions.
“The study demonstrates the power of the data,” said co-corresponding author Jinghui Zhang, chair of the St. Jude Department of Computational Biology. “If you don't have a sufficient number of patient samples, you lack the statistical power to find drivers present at a low prevalence. Once we had the power, we found a subgroup of new drivers involved in ALL development. The new drivers included a type of protein modification, which was really exciting, because we have never anticipated in the past that this group of proteins will be involved in disease initiation for leukemia.”
According to the study published in Nature Genetics, the researchers also found differences in the mutations present in subtypes of ALL, which may affect clinical care. For example, two of these groups involved specific genetic rearrangements that differed by CEBPA/FLT3 or NFATC4 gene expression. This observation may have clinical implications, as new FLT3 inhibitors are in clinical trials, suggesting the CEBPA/FLT3 ALL subtypes may be sensitive to such therapies, but the other subgroup may not be.
The study also revealed the sequence of mutation events in many ALL cases, which has been a long-standing question. Understanding this process would provide important insights into how leukemia develops, as well as better treatment options.
Information courtesy of St. Jude.