Scientists have created a road map of the genetic mutations present in the most common childhood cancer, acute lymphoblastic leukemia (ALL). The study by the Children’s Research Hospital St. Jude is the first to provide a comprehensive view of the genomics of all subtypes of ALL. The work serves as an essential guide for doctors and scientists to understand disease progression and improve treatment outcomes. The study was published today in Natural genetics.
“In this study, we were able to comprehensively define the number and type of recurrently altered genes that are found in childhood ALL,” said co-author Charles Mulligan, Ph.D., MBBS, Department of Pathology at St. Jude. “Because of the scale of the study, we could identify many new genes involved that have not been reported in leukemia or cancer at all, and show that they fall into several new cellular pathways.”
Creating a roadmap for understanding ALL
Thanks to the work of scientists and clinicians at institutions such as St. Jude, most children with ALL will survive. However, some of these patients do not respond well to therapy. The scientists believe that differences in the cancer genetics of these patients may predict responses to treatment. For example, the team of St. Jude found that in leukemia, which is generally considered low-risk, a specific genetic rearrangement is associated with a significantly increased risk of relapse.
If researchers understand the impact of genetic differences on cancer outcomes, then in the future doctors may be able to determine the sequence of patients’ cancers before starting treatment. This will allow doctors to customize treatment for individual patients 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 different subtypes of the disease.
“The findings of this study clearly define many distinct genetic subtypes of ALL,” said co-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 short- and long-term adverse effects of treatment.”
The study was unique because it included 2,574 samples from pediatric ALL patients, the largest such cohort ever published. By comparison, earlier studies typically examined hundreds of samples or fewer. St. Jude researchers collaborated 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. Researchers compare the sequences to find patterns in the mutations. These models can serve as road maps to understand how cancer develops and how it may respond to treatment.
“The study demonstrates the power of data,” said co-author Jinghui Zhang, Ph.D., chair of the Department of Computational Biology at St. Jude. “If you don’t have a sufficient number of patient samples, you lack the statistical power to detect drivers present at low prevalence. Once we got the power, we found a subset of new engines involved in ALL of the development.”
“The new drivers involved a type of protein modification, which was really exciting because we never expected in the past that this group of proteins would be involved in disease initiation for leukemia,” she said.
A series of intriguing results
The researchers, led by co-authors Sam Brady, Ph.D., and Kathryn Roberts, Ph.D., of St. Jude, were looking for new 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 potentially promote cancer development. Seventy of the genes have never been implicated in ALL. Some of the unexpected potential driver mutations are in genes involved in cellular processes such as ubiquitination, SUMOylation or non-coding cis-regulatory regions.
The researchers also found differences in the mutations present in ALL subtypes, which could affect clinical care. For example, two of these groups involve specific genetic rearrangements that differ in CEBPA/FLT3 or NFATC4 gene expression. This observation may have clinical implications, as new FLT3 inhibitors are in clinical trials, suggesting CEBPA/FLT3 ALL subtypes may be sensitive to such therapies, but the other subtype may not.
ALL cancer development begins with a chromosomal ‘Big Bang’
The researchers’ work revealed the sequence of mutational events in many ALL cases, with potential implications for treatment. In hyperdiploid B-cell ALL (B-ALL), the cancer cells have at least five more chromosomes than normal (46 in humans). A long-standing question is 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 sequence of events leading to hyperdiploid ALL using computational modeling of the sequence of mutations and chromosomal amplification data. This showed that in most hyperdiploid B-ALL cases, chromosomal gains appear to occur early and all at once, a chromosomal “big bang.” The precancerous cells then acquire more mutations, in part due to DNA damage caused by ultraviolet (UV) light. The finding shows that UV damage contributes to the development of ALL, a previously controversial idea.
Other scientists have access to the data from the St. Jude cloud article within the Pediatric Cancer Data Portal (PeCan).
This study is dedicated to co-author Daniela S. Gerhardt, PhD, former director of the Office of Cancer Genomics at the National Cancer Institute, who worked tirelessly to obtain the support necessary for this study and passed away in June 2021.