Scientists from St. Jude’s Children’s Hospital have created a roadmap of the 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 supply a comprehensive view of the genomics of all subtypes of ALL. The work serves as a foundational guide for physicians and scientists to understand disease development and improve treatment outcomes. The research was published in Nature Genetics. The research was titled: “The genomic landscape of pediatric acute lymphoblastic leukemia”.
“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-corresponding author Charles Mulligan, Ph.D., M.B.B.S., St. Jude Department of Pathology. “Because of the scale of the study, we could identify many newly implicated genes that have not been reported in leukemia or cancer at all, and to show that they fall into several new cellular pathways.”
If researchers understand the impact of genetic differences on cancer outcomes, then in the future, physicians can sequence patients’ cancer before starting treatment. This will enable physicians to personalize treatments to individual patients based on their genetics and likelihood of responding to different anti-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 diverse disease subtypes.
“The findings from this study clearly define many different genetic subtypes of ALL,” said co-corresponding author Stephen P. Hunger, M.D., 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 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 research was unique because it included 2,574 pediatric ALL patient samples, the largest such cohort ever published. As a comparison, earlier studies have typically studied hundreds of samples, or fewer. St. Jude investigators collaborated with the Children’s Oncology Group to collect samples over more than a decade.
The samples were subjected to a combination of whole genome, whole exam or transcriptome sequencing. The researchers compared the sequences to find patterns in the mutations. These patterns can serve as roadmaps to understand how the cancer develops and how it may respond to treatment.
The researchers, led by co-first-authors Sam Brady, Ph.D., and Kathryn Roberts, Ph.D., of St. Jude, looked for new driver mutations. On average, the pediatric cancer samples had four mutations that drove the development of ALL.
Overall, the group identified 367 significantly mutated genes that powerfully drive cancer development. Seventy of the genes have never been implicated with cellular processes such as ubqiquitination, SUMOylation, or non-coding cis-regulatory regions.
The researchers also found differences in the mutations present in subtypes of ALL, which may affect clinical care. For example, two of these groups 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 researchers’ work revealed the sequence of mutation events in many ALL cases, 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 insights into how leukemia develops.
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