(L to R) Co-first author Yuan Feng, PhD, corresponding author Xiaotu Ma, PhD, and co-first author Hanxia Li, PhD, all of the St. Jude Department of Computational Biology.
Some cases of the most common childhood cancer, B-cell acute lymphoblastic leukemia (B-ALL), return after treatment — and genetic changes present from the start may help explain why. Scientists at St. Jude Children’s Research Hospital and Seattle Children’s Hospital, in collaboration with the Children’s Oncology Group, found that mutations in a patient’s original tumor can be associated with relapse risk, and that these changes differ by leukemia subtype. The findings, published today in Blood, could help researchers better estimate and adjust for relapse risk before treatment begins.
More than 90% of patients with B-ALL survive with modern treatments, but outcomes are worse when the disease returns, indicating a need to prevent relapse. B-ALL is already categorized into subtypes based on the genetic changes that drive the cancer, which help guide treatment. However, the researchers wanted to understand whether additional genetic features could help explain relapses and be used to better tailor therapy.
“We verified that some tumors are born more resistant to conventional therapy,” said corresponding author Xiaotu Ma, PhD, St. Jude Department of Computational Biology. “By identifying the resistance mutations that are already present in the original tumor, we may also have found a better way to stratify patients into higher-intensity treatments to prevent those relapses from ever occurring.”
The researchers uncovered these mutations by comparing the DNA from diagnosis and relapsed samples of 183 pediatric B-ALL cases, the largest study of its kind, enabling subtype-level analysis. The findings suggest that the significance of a mutation must be considered in the context of the disease’s other genetic features.
“That was surprising,” Ma said. “We had expected to find some mutations that universally increased risk across subtypes, but this large cohort revealed that mutations can have a subtype-specific risk.”
Looking for relapse clues within leukemia subtypes
One example emerged in the ETV6::RUNX1 subtype, which is usually associated with a good prognosis. Within the subtype, the scientists discovered that patients with exon 5 of ETV6 fused with exon 4 of RUNX1 had a significantly higher risk of relapse than those with exon 5 of ETV6 fused with exon 3 of RUNX1, a dominant fusion transcript among this subtype.
“Clinically, this is important because patients with these features also relapsed faster than those without them,” said first author Yuan Feng, PhD, St. Jude Department of Computational Biology. “In the future, information may help clinicians decide what kind of treatment protocols should be used, as quicker relapse is associated with more aggressive disease. So, a higher intensity therapy may be called for in these patients.”
The team also identified genetic markers associated with greater relapse risk in other subtypes. That collection of mutations provides a roadmap to predict which patients at diagnosis are at the highest risk of recurrence better.
When relapse is not relapse
The genomic comparisons also revealed that about 3% of cases classified as relapses in this cohort were not a return of the original leukemia. Instead, they looked more like new cancers, sometimes driven by a genetic predisposition or other factors.
“These events were documented as clinical relapses, but our analysis showed that biologically they were second, unrelated cancers,” said co-first author Hanxia Li, PhD, St. Jude Department of Computational Biology. “That matters for treatment because if we know a patient has a new cancer, then they do not need a high-intensity relapse protocol; a frontline protocol with fewer long-term side effects can likely cure them.”
Collectively, the findings highlight the value of examining genetic changes already present at diagnosis, rather than mutations that arise during therapy.
“Our findings open the possibility of finding clinically actionable genomic insights that can improve and protect patient well-being from initial diagnosis,” Ma said. “In the future, that may help clinicians prevent relapse before it starts.”
Authors and funding
The study’s other co-first authors are Heather Mulder and Ying Shao, St. Jude. The study’s other co-corresponding author is Mignon Loh, Seattle Children’s Hospital / University of Washington. The study’s other authors are Emily Plyler, Yanling Liu, Pandurang Kolekar, Samuel Brady, Daniel Putnam, Monta Briviba, Quang Tran, Zhikai Liang, Li Fan, Scott Foy, Ti-Cheng Chang, Wenan Chen, Stanley Pounds, Gang Wu, Xiang Chen, Charles Mullighan, John Easton and Jinghui Zhang, St. Jude; Tyler Jones, Andrea McBride, Alexis Eckert and Christian Deardorff, Nationwide Children’s Hospital; Alexandra Stellwagen, University of Richmond; Lingyun Ji, University of Southern California; Laura Hogan, Stony Brook Children’s; Teena Bhatla, Children’s Hospital of New Jersey at Newark Beth Israel Medical Center; Deepa Bhojwani, Children’s Hospital Los Angeles; Karen Rabin, University of California San Francisco; Mary Shago, The Hospital for Sick Children; Andrew Carroll, University of Alabama at Birmingham; Stephen Hunger and David Teachey, Children’s Hospital of Philadelphia; William Carroll, New York University Medical Center and Patrick Brown, BeOne Medicines.
The study was supported by grants from the National Cancer Institute (R01CA273326, R01CA293587, National Clinical Trials Network (NCTN) Operations Center Grant U10CA180886, NTCN Statistics and Data Center Grant U10CA180899 and P30CA021765), the St. Baldrick’s Foundation, and the Fund for Innovation in Cancer Informatics and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children’s Research Hospital is leading the way the world understands, treats, and cures childhood catastrophic diseases. As the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children, St. Jude advances groundbreaking research and shares its discoveries worldwide to accelerate progress in pediatric medicine. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to more than 80% since the hospital opened more than 60 years ago. Through collaboration and innovation, St. Jude is working to ensure that children everywhere have access to the best possible care. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.