Infants who develop leukemia during the first year of life inherit a combination of genetic variations that can make them highly susceptible to the disease, according to a study published in Leukemia.
Results of whole-exome sequencing suggested that infants with leukemia inherited genetic variants from both parents that, by themselves, would not cause leukemia but, in combination, put the infants at high risk of developing the disease.
“We sequenced every single gene and found that infants with leukemia were born with an excess of damaging changes in genes known to be linked to leukemia,” said study author Todd Druley, MD, PhD, of Washington University School of Medicine in St Louis, Missouri.
“For each child, both parents carried a few harmful genetic variations in their DNA, and, just by chance, their child inherited all of these changes.”
However, it’s unlikely that the inherited variations alone cause leukemia, Dr Druley said. The infants likely needed to accumulate a few additional variations.
To uncover these findings, Dr Druley and his colleagues performed whole-exome sequencing in infants with acute myeloid leukemia (AML), infants with acute lymphoblastic leukemia (ALL), and the mothers of these children. The researchers used the process of elimination to determine a father’s contribution to a child’s DNA.
Among the 23 families studied, there was no history of pediatric cancers. As a comparison, the researchers also sequenced the DNA of 25 healthy children.
The team found the average amount of congenital coding variations was higher in infants with leukemia than in their mothers or the control subjects. The average total variants per exome was 1264.4 in infants with ALL, 1112.6 in their mothers, 2549.9 in infants with AML, 1225.0 in their mothers, and 582.8 in healthy controls.
The researchers then decided to home in on variants that were likely to impart a functional effect associated with leukemia. Using the COSMIC database, the team identified 126 ALL-associated genes and 655 AML-associated genes.
They found an average of 12.1 variants per ALL patient in the ALL-associated genes and 163.4 variants per AML patient in the AML-associated genes. There were 6.4 ALL-associated variants in the ALL patients’ mothers, 132.5 AML-associated variants in the AML patients’ mothers, 1.9 ALL variants in controls, and 27.5 AML variants in controls.
To prioritize genes that might be most relevant to infant leukemia, the researchers looked for compound heterozygous genes and the genes that were most commonly variant in all patients.
All of the infants with AML and 50% of the infants with ALL were compound heterozygotes for MLL3. Sixty-seven percent of AML patients were compound heterozygotes for RYR1 and FLG, and 50% of ALL patients were compound heterozygotes for RBMX.
The most variant (but not necessarily compound heterozygous) AML-associated genes in infants with AML were TTN, MLL3, and FLG. But the ALL-associated genes MDN1, SYNE1, and MLL2 were frequently variable in AML patients as well.
For infants with ALL, MDN1 was the most variable ALL-associated gene. But these infants also had frequent variations in the AML-associated genes TTN, RBMX, and MLL3.
Dr Druley and his colleagues plan to study these variations in more detail to understand how they contribute to infant leukemia development.
