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Landmark Genetic Study Aims To Wipe Common Childhood Cancer Off the Map

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Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Now, researchers at the St. Jude Children’s Research Hospital have created a roadmap of the genetic mutations present in patients with ALL.

The study, published today in Nature Genetics, is the first to offer a thorough view of the genetics underpinning every ALL subtype. This work aims to provide a functional guide for doctors and scientists, increasing our understanding of ALL and improving patient outcomes.

“In this study, we were able to comprehensively define the number and type of recurrently altered genes that are found in childhood ALL,” explained Dr. Charles Mullighan, co-corresponding author and medical director of the St. Jude Biorepository. “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 show that they fall into several new cellular pathways.”

Gathering the largest cohort of pediatric ALL samples

Most children diagnosed with ALL will survive, thanks to research breakthroughs from across the world increasing our understanding of the disease. Nevertheless, a small percentage of ALL patients do not respond to therapy. Researchers hypothesize that it may be possible to predict treatment outcomes by studying differences in the genetic makeup of the cancers in these poor responders. This is evidenced by previous findings from the St. Jude team, which showed that a specific single genetic error was enough to significantly increase the risk of relapse in a type of leukemia that is normally considered low risk.

With better knowledge of how genetic differences influence responses to cancer treatment, physicians in the future will be able to sequence a patient’s cancer prior to treatment. Patients could then receive personalized treatments tailored to them, based on which ones will be effective for their particular genetic profile. However, before this can become a reality, we need to know which mutations are responsible for driving leukemia development by creating a genetic “roadmap”.

In the current study, researchers gathered samples from over 2,500 pediatric ALL patients, creating the largest cohort of its type to be published (earlier studies collected only a few hundred samples or sometimes even fewer). Once all samples were collected, they were analyzed using next-generation sequencing techniques such as whole-genome, whole-exome and transcriptome sequencing.

What is next-generation sequencing?

Next-generation sequencing (NGS) is a laboratory technique that determines the sequence of the genetic code that makes up DNA or RNA. This data can then be used to work out which mutations are associated with different diseases or conditions.

Chair of the St. Jude Department of Computational Biology and co-corresponding author Dr. Jinghui Zhang explained the importance of a study of this size: “The study demonstrates the power of the data. 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.”

Which mutations drive ALL?

The researchers analyzed the sequencing results to find any patterns in the mutations they found, using them to draw a map that shows how these cancers develop and which treatments might be effective against them. This data allowed them to identify mutations that drive the progression of ALL – on average, each pediatric ALL sample had four of these driver mutations. In total, 376 significantly mutated driver genes were identified across all the samples – and of these, 70 had never before been linked to ALL, and many were linked to unexpected cellular processes.

Co-corresponding author Dr. Stephen P. Hunger summarized some of the findings from the study. “The findings from this study clearly define many different genetic subtypes of ALL,” he explained. “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 researchers were also able to put together a series of mutational events that occur in many cases of ALL. By looking at cells from so-called hyperdiploid B-cell ALL (which have at least five more chromosomes than normal), the team used computational techniques to put together a timeline of the various mutations and chromosomal gains to get some insight into how leukemia develops. This timeline showed that in most of these cases, cells undergo a “big bang” of changes early on in their cancerous development in which many chromosomal gains occur all at the same time. In a somewhat more controversial finding, the results also indicated that abnormal cells then accumulate more mutations through damage caused by UV radiation.

The data from this study has been made available for use by other scientists within the pediatric cancer data portal on the St. Jude Cloud.

Reference: Brady SW, Roberts KG, Gu Z, et al. The genomic landscape of pediatric acute lymphoblastic leukemia. Nat. Genet. 2022:1-14. doi: 10.1038/s41588-022-01159-z

This article is a rework of a press release issued by St. Jude Children's Research Hospital. Material has been edited for length and content.