Inherited Gene Variation Linked to Relapsing Pediatric Leukemia

Genomic profiling of childhood acute lymphoblastic leukemia (ALL) identified a high-risk subtype with an expression signature resembling that of Philadelphia chromosome-positive ALL (Ph-like ALL) which is often fatal.

Collaborating scientists led by those at St. Jude Children's Research Hospital (Memphis, TN, USA) used a library of 718,890 common genetic variations known as single nucleotide polymorphisms, or SNPs, to screen the DNA of 75 children with Ph-like ALL, 436 children with other ALL subtypes and 6,661 individuals without ALL.

Genome-wide SNP genotyping was performed using the Affymetrix Human SNP Array 6.0 (Affymetrix; Santa Clara, CA, USA) and a custom-designed oligonucleotide tiling array (Agilent Technologies; Santa Clara, CA, USA) were used to detect the Ikaros family zinc finger protein 1 (IKZF1) gene deletion in diagnostic ALL blast cells. Polymerase chain reaction and Sanger sequencing were also performed.

Of the patients with Ph-like ALL, 58% carried the high-risk version of the gene, compared to 29% of patients with other ALL subtypes and 20% of those without ALL. When the team checked for the high-risk variant in additional patients with the Ph-like ALL subtype as well as other young ALL patients and individuals without the disease, they found a similar proportion carried the high-risk version.

The scientists identified a significant percentage of patients with the high-risk that the gene encoding for Trans-acting T-cell-specific transcription factor GATA-3 (GATA3) variant also had the tumor genetic alterations, including mutations, gene deletions, and chromosomal re-arrangements that are the hallmark of Ph-like ALL. The changes occur in other genes, including those that regulate how blood cells grow and mature. While overall cure rates for pediatric ALL are now about 90%, only 63% of children with Ph-like ALL are alive and cancer free after five years.

Jun J. Yang, PhD, the senior author of the study said, “Until recently, little was known about why a child develops a specific subtype of ALL in the first place and whether inherited genetic variations that predispose an individual to a subtype also influence how he or she responds to the therapy. In this study, we discovered a genetic basis for susceptibility to Ph-like ALL, but even more importantly, the evidence that host and tumor genomes may interact with each other to influence the risk of developing and surviving ALL.” The study was published on October 20, 2103, in the journal Nature Genetics.

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St. Jude Children's Research Hospital
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