Landmark genetic study aims to wipe common childhood cancer off the map

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

The study, published today in Natural genetics, is the first to offer an in-depth view of the genetics underlying each ALL subtype. This work aims to provide a functional guide for physicians 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 found in childhood ALL,” explained Dr. Charles Mullighan, corresponding co-author and medical director of St. Jude Biorepository. “Due to the breadth 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 belong to several new cellular pathways.”

Gathering the largest cohort of pediatric ALL specimens

Most children diagnosed with ALL will survive, thanks to research breakthroughs around the world that are improving our understanding of the disease. Nevertheless, a small percentage of ALL patients do not respond to treatment. The researchers hypothesize that it might be possible to predict treatment outcomes by studying differences in the genetic makeup of cancers in these poor responders. This is evidenced by previous findings by the St. Jude team, which showed that a single specific genetic error was sufficient 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, doctors of the future will be able to sequence a patient’s cancer before 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 becomes a reality, we need to know which mutations are responsible for the development of leukemia by creating a genetic “road map”.

In the current study, researchers collected samples from over 2,500 pediatric ALL patients, creating the largest such cohort to be published (previous studies collected only a few hundred samples or sometimes even fewer). ). Once all the 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 determine which mutations are associated with different diseases or conditions.

St. Jude’s Department of Computational Biology Chair and corresponding co-author Dr. Jinghui Zhang explained the importance of a study of this size: “The study demonstrates the power of data. If you don’t have a sufficient number of patient samples, you don’t have the statistical power to find drivers present at a low prevalence. Once we had the power, we found a subgroup of new pilots involved in the development of ALL.

What mutations cause ALL?

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

Corresponding co-author Dr. Stephen P. Hunger summarized some of the findings of the study. “The results of 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 side effects of treatment.

The researchers were also able to establish a series of mutational events that occur in many cases of ALL. By examining cells of so-called hyperdiploid B-cell ALL (which have at least five more chromosomes than normal), the team used computational techniques to establish a timeline of the various mutations and chromosome gains in order to have a insight into how leukemia develops. This timeline showed that in most of these cases, cells experience a “big bang” of changes early in their cancerous development in which many chromosomal gains occur at the same time. In a slightly more controversial finding, the results also indicated that abnormal cells then accumulate more mutations due to UV damage.

Data from this study has been made available for use by other scientists in the Childhood 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. Broom. 2022:1-14. doi: 10.1038/s41588-022-01159-z

This article is a reworking of a press release published by St. Jude Children’s Research Hospital. Material has been edited for length and content.

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