Association Is Found Between Bone Complications in Young Pediatric Patients With Leukemia and Gene Variations

ORLANDO, FL—Variations in genes involved in normal bone development are associated with an 8- to 15-fold increased risk for osteonecrosis in young patients with acute lymphoblastic leukemia (ALL), according to research led by St. Jude Children's Research Hospital and Children's Oncology Group investigators. The results were presented at the 57th American Society of Hematology (ASH) Annual Meeting.

Osteonecrosis is a major adverse effect of chemotherapeutic treatment of ALL. Approximately 15% of patients with ALL develop the condition, which is caused by reduced blood flow to bones in the hips and other joints leading to breakdown of bone faster than it is replenished. Patients' symptoms may include stiffness, pain, and disability, and may necessitate joint-replacement surgery. Patients with ALL age 10 to 20 years are at particularly high risk for osteonecrosis.

This study is the first to focus on the genetic risk factors for osteonecrosis in patients with ALL who are younger than 10 years, an age group that accounts for approximately 75% of newly identified ALL and approximately half of those with ALL who develop osteonecrosis. Researchers used genome-wide association studies to review the DNA of 1186 patients with ALL younger than 10 years for single changes in the 3.2 billion chemical bases (letters) that make up the human genetic code.

Researchers were looking for genetic variations that occurred more often in 82 young patients with ALL who developed osteonecrosis than in 287 who did not develop the condition. The screening was then repeated with an additional 817 patients younger than 10 years with ALL. The patients were treated in clinical trials of the Children's Oncology Group, an international clinical trials group.

Patients with osteonecrosis were 8 to 15 times more likely to have genetic variations located near BMP7, a gene important to normal bone development.

"The goal of this and earlier studies is to identify and understand genetic and other risk factors for osteonecrosis so we can identify patients at high risk for the side effect and develop interventions to prevent the disease," said Seth Karol, MD, a St. Jude Physician Scientist Training Program fellow and first author of the study. Karol works with the study's senior author Mary Relling, PharmD, chair of the St. Jude Department of Pharmaceutical Sciences.

A variation in the glutamate receptor gene GRID2 was also associated with a greater likelihood of osteonecrosis in ALL patients younger than 10 years. GRID2 belongs to a family of genes that carries instructions for assembling receptor proteins on the cell membrane that cells rely on to respond to the chemical messenger glutamate. The finding confirms previous research reporting on the association between variations in glutamate receptor genes and an increased risk of osteonecrosis; the prior study primarily identified the risk in patients age 10 years and older.

"The finding that the genetic variations that affect osteonecrosis risk differ by age was unexpected," Karol said. "The results suggest that as children age, particularly when bone growth is accelerated during adolescence, certain gene variants may become more or less important."

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