Concurrent Germline RB1 & Mosaic TP53 in a Child With Multiple Childhood Cancers.
This report describes a child with a pathogenic germline RB1 variant and fibroblast-confirmed low-level TP53 mosaicism who developed retinoblastoma, osteosarcoma, and MDS progressing to AML before age 6.
Open original publication →What the AI sees
This report describes a child with a pathogenic germline RB1 variant and fibroblast-confirmed low-level TP53 mosaicism who developed retinoblastoma, osteosarcoma, and MDS progressing to AML before age 6.
Research significance
The reported findings establish coexisting RB1-associated predisposition and TP53 mosaicism in this patient; they support, but do not prove, the hypothesis that combined predisposition intensified cancer risk and possibly treatment-related vulnerability, which could eventually inform surveillance and treatment-planning strategies.
Source abstract
We report a patient with a pathogenic germline variant (PGV) in RB1 and somatic mosaicism for a pathogenic TP53 variant who developed three distinct types of childhood cancer: retinoblastoma, osteosarcoma, and myelodysplastic syndrome (MDS) before the age of 6 years. The patient presented with bilateral retinoblastoma at age 4 weeks and a PGV in RB1 was found. At the very young age of 3 years, she developed an osteosarcoma. A pathogenic variant in TP53 was initially found in bone marrow as part of the diagnostic workup for the patient's third cancer, MDS rapidly progressing to acute myeloid leukemia (AML). Due to the unusual clinical phenotype, cultured fibroblasts from a skin biopsy were examined and identified somatic TP53 mosaicism, with a VAF of 7%. The early debut of osteosarcoma at age 3 years indicates a stronger predisposition than only heritable retinoblastoma would explain, but the development of subsequent MDS could implicate a vulnerability to chemotherapy due to digenic cancer predisposition. This unusual clinical course underlines the need for a better understanding of genetic predisposition to cancer and the interplay between genetic predisposition and treatment effects in optimizing therapeutic strategies and improving long-term outcomes for these patients.