Scientists have created a roadmap of genetic mutations present in the most common childhood cancer, acute lymphoblastic leukemia (ALL). The St. Jude Children’s Research Hospital study is the first to provide a comprehensive view of the genomics of all ALL subtypes. The work serves as a fundamental guide for physicians and scientists to understand disease development and improve treatment outcomes. The research was published today in Natural genetics.
In this study, we were able to comprehensively define the number and type of recurrently altered genes found in childhood ALL. Due to the scale of the study, we were able to identify many newly implicated genes that have not been reported in leukemia or cancer at all, and show that they fall into several new cellular pathways.
Charles Mullighan, Ph.D., MBBS, corresponding co-author, St. Jude Department of Pathology
Create a roadmap to understand EVERYTHING
Thanks to the work of scientists and clinicians at institutions like St. Jude, most children with ALL will survive. However, a fraction of these patients do not respond well to treatment. Scientists believed that differences in the cancer genetics of these patients could predict responses to treatment. For example, the St. Jude team found that in leukemia which is normally considered low risk, a single specific genetic rearrangement was associated with a significantly increased risk of relapse.
If researchers understand the impact of genetic differences on cancer outcomes, then future doctors will be able to sequence patients’ cancer before starting treatment. This will allow doctors to customize treatments for each patient based on their genetics and likelihood of responding to different cancer therapies.
But before bringing personalized therapies into the clinic, scientists need to map the different mutations that drive the development of leukemia across the landscape of various disease subtypes.
“The results of this study clearly define many different genetic subtypes of ALL,” said co-corresponding author Stephen P. Hunger, MD, Children’s Hospital of Philadelphia. “Several of these genetic subtypes were previously unknown, and we also identified common secondary and tertiary mutations that lead to the development of ALL. We were able to identify new pathways to target with precision medicine treatments to potentially improve cure rates and reduce long-term adverse effects of treatment.”
The research was unique because it included 2,574 samples from pediatric ALL patients, the largest such cohort ever published. For comparison, previous studies have typically looked at hundreds of samples or even fewer. St. Jude investigators have worked with the Children’s Oncology Group to collect samples for more than a decade.
Samples were subjected to a combination of whole genome, whole exome or transcriptome sequencing. The researchers compared the sequences to find patterns in the mutations. These models can serve as roadmaps for understanding how cancer develops and how it may respond to treatment.
“The study demonstrates the power of data,” said co-corresponding author Jinghui Zhang, Ph.D., chair of St. Jude’s Department of Computational Biology. “If you don’t have a sufficient number of patient samples, you don’t have the statistical power to find drivers present at low prevalence. Once we had the power, we found a sub- group of new drivers involved in the development of ALL.”
“The new drivers included a type of protein modification, which was really exciting because we never anticipated in the past that this group of proteins would be involved in the initiation of leukaemia,” she said. .
A series of intriguing results
The researchers, led by co-first authors Sam Brady, Ph.D., and Kathryn Roberts, Ph.D., of St. Jude, searched for novel driver mutations. On average, pediatric cancer samples had four mutations that led to the development of ALL.
Overall, the group identified 376 significantly mutated genes that could lead to cancer development. Seventy of the genes have never been implicated in ALL. Some of the unexpected potential motor mutations are in genes involved in cellular processes such as ubiquitination, SUMOylation or non-coding cis-regulatory regions.
The researchers also found differences in mutations present in ALL subtypes, which may affect clinical care. For example, two of these groups involved specific genetic rearrangements that differed in CEBPA/FLT3 Where NFATC4 gene expression. This observation may have clinical implications, as new FLT3 inhibitors are undergoing clinical trials, suggesting the CEBPA/FLT3 ALL subtypes may be sensitive to these therapies, but the other subgroup may not be.
The development of ALL cancers begins with a chromosomal “big bang”
The researchers’ work revealed the sequence of mutation events in many cases of ALL, with potential implications for treatment. In hyperdiploid B-cell ALL (B-ALL), cancer cells have at least five more chromosomes than normal (46 in humans). A long-standing question has been the relative timing of chromosomal gains and other mutations in the development of hyperdiploid ALL. Understanding this process would provide important insight into how leukemia develops.
The researchers traced the order of events leading to hyperdiploid ALL using computer modeling of the mutation sequence and chromosome gain data. This showed that in most cases of hyperdiploid B-ALL, chromosome gains seem to occur early and all at once, a chromosome “big bang”. Then, precancerous cells acquire more mutations, in part due to DNA damage induced by ultraviolet (UV) light. The finding shows that UV damage contributes to the development of ALL, a previously controversial notion.
Other scientists can access the article’s data on the St. Jude Cloud, in the Pediatric Cancer Data Portal (PeCan) database.
This study is dedicated to co-author Daniela S. Gerhard, Ph.D., former director of the Office of Cancer Genomics at the National Cancer Institute, who worked tirelessly to gain the necessary support for this study and is passed away in June 2021.
St. Jude Children’s Research Hospital
Brady, SW, et al. (2022) The genomic landscape of pediatric acute lymphoblastic leukemia. Natural genetics. doi.org/10.1038/s41588-022-01159-z.