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Subset of Childhood ALL Cases Marked by Germline TP53 Mutations

NEW YORK (GenomeWeb) – Germline mutations affecting TP53 may predispose some children to forms of acute lymphoblastic leukemia (ALL) with relatively poor prognoses, new research suggests.

Following from past studies hinting that pediatric hypodiploid ALL may involve some of the same germline mutations linked to the Li-Fraumeni cancer predisposition syndrome, researchers from St. Jude Children's Research Institute and elsewhere did targeted TP53 sequencing on samples from more than 3,800 children with ALL. The search unearthed 22 rare, pathogenic mutations in TP53 coding sequences and dozens more non-silent changes in the gene.

The team noted that the 77 ALL-affected children carrying germline TP53 changes were older when diagnosed with the disease — closer to 16 years old, rather than seven (the average age at ALL diagnosis in the TP53 mutation-free cases). Overall survival times and event-free survival times dipped alongside these alterations, while secondary cancers rose, occurring in one-quarter of the ALL cases with TP53 mutations, but fewer than 1 percent of those without.

Based on their findings, senior author Jun Yang, a pharmaceutical sciences, oncology, and hematological malignancies researcher at St. Jude, and his colleagues wrote in their Journal of Clinical Oncology study that "[l]oss-of-function germline TP53 variants predispose children to ALL and to adverse treatment outcomes of ALL therapy, particularly the risk of second malignant neoplasms."

Using targeted sequencing, the researchers assessed germline TP53 sequences in 3,801 children who had been recently diagnosed with B-cell ALL and were participating in Children's Oncology Group trials. After annotating germline variants in the gene and comparing them with those in TP53 sequences from more than 60,700 individuals in the Exome Aggregation Consortium, they narrowed in on 49 non-silent, suspicious changes in TP53 in the germlines of 77 children with B-cell ALL.

The team deemed 27 of the TP53 changes as variants of uncertain significance. The other 22 variants — which were missing or found at extremely low allele frequency in control individuals without known ALL diagnoses, but found in 26 ALL-affected study participants — were classified as pathogenic.

Along with their over-representation in children who were older at the time of ALL diagnoses, the pathogenic TP53 mutations appeared to be more common in the germlines of children with hypodiploid ALL, the researchers reported, a form of ALL marked by missing chromosomes and poorer outcomes.

Whereas just over 1 percent of the pediatric ALL patients with wild type germline TP53 had been diagnosed with hypodiploid ALL, they noted, the hypodiploid diagnoses climbed to 3.9 percent in children with TP53 VUS and to more than 65 percent in those carrying the pathogenic germline glitches in the tumor suppressor gene.

The team saw still other causes for concern in the ALL patients with pre-existing TP53 mutations, including poorer post-treatment outcomes and a dramatic jump in secondary cancers (affecting 25.1 percent of the ALL patients with pathogenic germline TP53 mutations, but just 0.7 percent without over five years). In a statement, Yang cautioned that treatments used to tackle their initial ALL "might have added to that risk, but we do not know for sure."

"The risk of inducing second cancers with total body irradiation-based preparative regimens presents a significant clinical conundrum," he and his colleagues wrote. "Questions remain though if other non-genotoxic therapeutic strategies are needed for this group of patients (e.g. immunotherapies)."