Pediatric Osteosarcoma Harbors a High Incidence of Pathogenic TP53 Variants

Brandon J. Diessner, PhD

TP53 was found to be the only gene with a germline de novo pathogenic or likely pathogenic variant in pediatric patients with osteosarcoma, according to findings from the Children’s Oncology Group that were published in JCO Precision Oncology.

Among 95 pediatric patients with osteosarcoma who underwent whole-exome sequencing, 61 de novo variants were identified in 60 genes (n = 47). Among all 240 pediatric patients with osteosarcoma, 5.4% (n = 13) harbored a pathogenic or likely pathogenic TP53 germline variant, of which nearly half (46.2%; n = 6) were de novo.

“A high proportion of rare pathogenic TP53 variants in the pediatric patients with osteosarcoma may be de novo,” Brandon J. Diessner, PhD, of the University of Minnesota, and co-study authors wrote. “The high proportion of de novo variants identified among those that are pathogenic suggests that relying on family history patterns of cancer to identify patients with osteosarcoma at risk of harboring pathogenic TP53 variants is insufficient.”

The study population comprised 240 pediatric patients with osteosarcoma who had been under the age of 20 years at diagnosis. In phase 1 of the study, 95 patients and their parents underwent whole-exome sequencing, and, in the phase 2 portion, 145 patients underwent targeted sequencing.

After recurrent rare variants from phases 1 and 2 were confirmed to be de novo or inherited via Sanger sequencing, the variants were categorized as pathogenic or likely pathogenic, variant of uncertain significance, likely benign, or benign.

Among the 61 de novo variants that were identified in phase 1, 1 was pathogenic and localized to HFE, 2 were likely pathogenic and localized to TP53, 2 were benign and localized to LEPR and FLG, 1 was a variant of uncertain significance and localized to SMARCA4, and 55 were not reported. Six variants were classified as having high impact, and 55 were classified as having moderate impact. Two patients in phase 1 had de novo variants in the TP53 gene; the other de novo variants were found only in 1 gene.

Among 145 patients who underwent targeted sequencing, an additional 11 TP53 germline variants were identified in 11 patients; 7 were pathogenic (4.8%; 95% CI, 2.0%-9.7%) and 4 were likely pathogenic (2.8%; 95% CI, 0.8%-6.9%).

Among all 240 patients, 13 (5.4%; 95% CI, 2.9%-9.1%) harbored a pathogenic (n = 7; 2.9%; 95% CI, 1.2%-5.9%) or likely pathogenic TP53 germline variant (n = 6; 2.5%; 95% CI, 0.9%-5.4%). Among the 13 TP53 variants, 6 were de novo (46.2%; 95% CI, 19.2%-74.9%). The percentage of de novo TP53 variants among all 240 patients was 2.5% (n = 6; 95% CI, 0.9%-5.4%).

Pathogenic and likely pathogenic TP53 variants were spread between amino acids 107 and 342. Among the 13 pathogenic and likely pathogenic TP53 variants, 10 (76.9%; 95% CI, 46.2%-95.0%) were missense variants that affected the DNA binding domain, 1 was a missense variant outside of the DNA binding domain (7.7%; 95% CI, 0.1%-36.0%; tetramerization domain), and 2 were nonsense variants (15.4%; 95% CI, 1.9%-4.5%).

Significant associations were not found between the set of 60 genes with a de novo variant in phase 1 (P = .91) or between clinical features and pathogenic and likely pathogenic TP53 germline variants. 

Three of the 13 patients with a pathogenic and likely pathogenic TP53 germline variant returned a questionnaire, indicating a family history that was consistent with the 2015 Revised Chompret criteria. None of these patients harbored a de novo pathogenic variant.

“The high proportion of de novo pathogenic or likely pathogenic TP53 germline variants observed suggests efforts to identify pediatric patients with osteosarcoma at risk of harboring pathogenic TP53 variants should continue to evolve, including possible universal screening for germline TP53 pathogenic or likely pathogenic variants among pediatric patients with osteosarcoma,” concluded the study authors. 

Reference:

Diessner BJ, Pankratz N, Hooten AJ, et al. Nearly half of TP53 germline variants predicted to be pathogenic in patients with osteosarcoma are de novo: a report from the Children’s Oncology Group. JCO Precis Oncol. 2020;4:1187-1195. doi:10.1200/PO.20.00087