NEW YORK (GenomeWeb) – Germline variants in the IKZF1 gene can increase the risk for familial and sporadic childhood acute lymphoblastic leukemia, according to new research by St. Jude Children's Research Hospital and collaborators.
The results of the study, led by co-senior authors and St. Jude researchers Jun Yang and Charles Mullighan, were published in Cancer Cell today.
"This will expand the number of genes to consider when screening for predisposition to leukemia, particularly B-ALL," said co-author Kim Nichols, director of the St. Jude Cancer Predisposition Division, in a statement. "And while not everyone carrying a germline IKZF1 variant will develop leukemia, these results will help us educate families about the potential risk of leukemia."
ALL is the most common childhood cancer and remains the leading cause of cancer death in children, despite cure rates of close to 90 percent.
While only a small percentage of cases are familial, germline mutations in three genes — TP3, PAX5, and ETV6 — had previously been shown to increase the risk for the cancer.
Also, somatic mutations in the IKZF1 gene, which encodes the lymphoid transcription factor IKAROS, had already been linked to poor therapy response in high-risk B-progenitor ALL, but the new study shows that the gene also plays a role in inherited disease risk.
The study started out with an index family with a protein-truncating germline variant in IKZF1 and two family members who died of B-ALL.
To examine the prevalence and nature of germline IKZF1 variants in other leukemia cases, the researchers performed targeted sequencing on DNA from almost 5,000 children with newly diagnosed presumed sporadic ALL who were enrolled in St. Jude Children's Research Hospital and Children's Oncology Group frontline clinical trials.
Forty-three additional patients, or 0.9 percent, turned out to have a total of 27 unique coding variants in IKZF1, including 25 missense and two nonsense variants. All variants except one were found in patients with B-cell, not T-cell, lineage ALL, and the variants were distributed across the length of the gene.
"This finding adds to the growing body of evidence that, while germline variations still account for a small percentage of pediatric ALL cases overall, more children than previously recognized inherit a predisposition to develop ALL," said Mullighan, a member of the St. Jude Department of Pathology, in a statement.
Further functional studies in mice and cell lines showed that 22 of the germline IKZF1 variants had an adverse effect on gene function and were thus classified as damaging, whereas six were designated benign.
Several of the IKZF1 germline variants also reduced responsiveness of leukemia cells to conventional chemotherapeutic agents, as well as to kinase inhibitors.
"The current study demonstrates the power of sequencing large cohorts of sporadic ALL cases for similar variants" compared to variants discovered in familial cases, the authors wrote.
While truly familial ALL is uncommon, they noted, "it is unclear whether relatives of the majority of patients with germline IKZF1 variants from the sporadic cohort are also at increased risk of ALL, as clinical records for the majority of such cases were not accessible."