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Jun J. Yang, PhD
Photo from Seth Dixon,
St. Jude Children’s
Research Hospital

New research has revealed germline variations associated with high-risk acute lymphoblastic leukemia (ALL) in children.

Researchers sequenced the TP53 tumor suppressor gene in nearly 4000 children with ALL and identified 22 pathogenic germline variants.

These variants were associated with inferior survival and an increased risk of developing second malignancies.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in the Journal of Clinical Oncology.

The researchers performed targeted sequencing of TP53 coding regions in 3801 children with ALL who were enrolled in 2 Children’s Oncology Group trials (AALL0232 and P9900).

The sequencing revealed 49 unique TP53 coding variants, which were found in 77 children. Twenty-two of the variants were pathogenic, and they were found in 26 children.

The researchers also analyzed data from 60,706 control subjects without ALL and found the 22 pathogenic variants were more likely to be found in the ALL patients than controls. The odds ratio was 5.2 (P<0.001).

Among the ALL patients, those who had the pathogenic variants were significantly older at diagnosis than those without the variants, with median ages of 15.5 years and 7.3 years, respectively (P<0.001).

The pathogenic variants were most common in patients with hypodiploid ALL. About 65% of patients who carried the pathogenic variants had hypodiploid ALL, as did 1.2% of children with wild-type genotype (P<0.001).

The pathogenic variants were associated with inferior event-free survival and overall survival as well. The hazard ratios were 4.2 (P<0.001) and 3.9 (P=0.001), respectively.

And the pathogenic variants were associated with a higher risk of second cancers. The 5-year cumulative incidence of second malignancies was 25.1% among patients with the pathogenic variants and 0.7% among patients without the variants (P<0.001).

“These germline variations are a double whammy for carriers,” Dr Yang said. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”

The association between the pathogenic variants and second cancers has prompted Dr Yang and his colleagues to explore ways to help patients manage their risk.

“Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” Dr Yang said. “I believe this finding may change treatment and follow-up for these high-risk patients.”

Dr Yang and his colleagues also noted that inherited variations in TP53 are a hallmark of Li-Fraumeni syndrome. And the syndrome might partially explain the high rate of second cancers in ALL patients with the pathogenic TP53 variants.

“The ALL treatment might have added to that risk,” Dr Yang said, “but we do not know for sure.”

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