Large-Scale Genomics Study Identifies Children With High-Risk Cancer

Acute lymphoblastic leukemia (ALL), a malignancy of the white blood cells, is a common childhood cancer. Understanding the genomic changes underlying ALL has led to the development of new, targeted therapies, especially for patients with high-risk subtypes. Although long-term survival for childhood ALL exceeds 85 percent, some subtypes are associated with a higher risk of relapse and death.

Philadelphia chromosome-like (Ph-like) ALL is a particularly aggressive form of B-cell ALL, accounting for 15 percent of childhood B-cell ALL and up to 25 percent of B-cell ALL in adolescents and young adults. Without targeted therapies, these patients historically have had a very poor outcome.

Ph-like ALL was so named because it has a gene expression profile similar to the historically recognized, Philadelphia chromosome-positive (Ph⁺) ALL subtype characterized by a translocation between chromosomes 9 and 22, forming a fusion between two genes (BCR-ABL1). Patients with Ph-like ALL lack this gene fusion but appear to have a variety of other genomic alterations that promote cell growth and malignant transformation

A large-scale collaborative effort that began five years ago and included researchers at Nationwide Children’s, the Children’s Oncology Group, St. Jude Children’s Research Hospital, and the University of New Mexico revealed a variety of novel genetic alterations that drive the Ph-likesubtype.

Shalini Reshmi, PhD, a Clinical Director within the Institute for Genomic Medicine at Nationwide Children’s, was a co-first author of the study. Dr. Reshmi, also an assistant professor of Pathology at The Ohio State University College of Medicine (OSUCOM), and her colleagues characterized the genomic alterations in samples from more than 1,300 high-risk childhood B-cell ALL patients. They identified multiple gene fusions and genomic rearrangements, many of them involving cytokine receptors or kinase signaling pathways. Based on the results of the study, the researchers devised a screening algorithm to determine downstream diagnostic testing to identify targetable genomic alterations suitable for additional treatment.

The findings of the study provided support for precision medicine testing and treatment of Ph-like ALL implemented by the Children’s Oncology Group. The findings laid the groundwork for two currently active clinical trials identifying patients in real time to administer targeted therapies.

“We are currently screening patients in real time to see if they have an identifiable Ph-like genomic lesion that would qualify them for additional therapies,” says Dr. Reshmi.

“This is an example of a large-scale genomics project actually leading to a change in care,” says Julie Gastier-Foster, PhD, senior director of the Institute for Genomic Medicine Clinical Laboratory at Nationwide Children’s and one of the study’s senior authors. “When they enroll, all of the kids with high-risk ALL are getting this testing routinely. It’s already been incorporated into patient care. What is important is that these are very targeted therapies that are now available to these patients. Since they have these genomic lesions, they can be given very specific drugs in addition to regular chemotherapy and it is saving lives.”

Dr. Reshmi explains that she and her colleagues are only at the beginning of identifying the genomic alterations associated with Ph-like ALL. While some of the alterations can be picked up by targeted and easily designed assays, many require larger scale, next generation sequencing assays to identify regions of the genome driving the disease.

“It can be frustrating at times because there are so many patients that we know have a Ph-like gene expression profile but in whom we are unable to determine the driving lesion due to the requirement of time sensitive identification for treatment. We have to complete all downstream testing within day 29 of the patient’s study enrollment,” says Dr. Reshmi.

In addition to quickly identifying the specific genomic alterations in cases of Ph-like ALL, the laboratorians hope to broaden the use of high-throughput genomic approaches to childhood cancers outside of ALL.

“It’s so gratifying for us to convert discoveries into patient diagnostics that actually impact how these kids are being treated,” says Dr. Gastier-Foster, who is also Clinical Professor of Pathology and Pediatrics at OSUCOM.

Reference:

Reshmi SC, Harvey RC, Roberts KG, Stonerock E, Smith A, Jenkins H, Chen I-M, Valentine M, Liu Y, li Y, Shao Y, Easton J, Payne-Turner D, Gu Z, Tran TH, Nguyen JV, Devidas M, Dai Y, Heerema NA, Carroll III AJ, Raetz EA, Borowitz MJ, Wood BL, Angiolillo AL, Burke MJ, Salzer WL, Zweidler-McKay PA, Rabin KR, Carroll WL, Zhang J, Loh ML, Mullighan CG, Willman CL, Gastier-Foster JM, Hunger SP. Targetable kinase gene fusions in high risk B-ALL: A study from the Children’s Oncology Group. Blood. 2017. doi: 10.1182/blood-2016-12-758979.

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