Abstract
Retinoblastoma (Rb) is a malignant tumor of the developing retina that affects children before the age of five years in association with inherited or early germline mutations of the RB1 gene. The genetic predisposition is also a driver for other primary malignancies, which have become the leading cause of death in retinoblastoma survivors. Other malignancies can occur as a consequence of radiotherapy. We describe a patient with retinoblastoma in which we detected a novel RB1 c.2548C > T, p.(Gln850Ter) and a synchronous MET c.3029C > T, p.(Thr1010Ile) mutation as well. After presenting with bilateral retinoblastoma, the patient developed at least four different manifestations of two independent osteosarcomas. Our goal was to identify all germline and somatic genetic alterations in available tissue samples from different time periods and to reconstruct their clonal relations using next generation sequencing (NGS). We also used structural and functional prediction of the mutant RB and MET proteins to find interactions between the defected proteins with potential causative role in the development of this unique form of retinoblastoma. Both histopathology and NGS findings supported the independent nature of a chondroblastic osteosarcoma of the irradiated facial bone followed by an osteoblastic sarcoma of the leg (tibia).
Highlights
Retinoblastoma (Rb, OMIM#180200) is a malignant tumor of the developing retina that affects children before the age of five years with an estimated incidence between1 in 16,000 and 1 in 18,000 live births [1]
The aims of our study were (i) to identify independent de novo second hits in a patient with bilateral Rb of nonparental origin; (ii) to exclude parental carrier status; (iii) to characterize histological and genetic features of samples originating from the two Rb and the four anatomically distinct osteosarcoma tumors; (iv) to identify genetic differences between the irradiation-related orbitofacial and the non-irradiation-related de novo osteosarcoma of the lower extremity; (v) to predict structure and function of the proteins encoded by the mutant genes, as reconstructed based on DNA sequencing; and, (vi) to identify potential interactions between defected proteins using prediction analysis
Seven formaldehyde-fixed paraffin-embedded tissue (FFPE) samples were tested from the patient diagnosed and treated with Rb/osteosarcoma between 2010 and 2019 at the Department of Pediatrics, University of Debrecen (Table 1)
Summary
Retinoblastoma (Rb, OMIM#180200) is a malignant tumor of the developing retina that affects children before the age of five years with an estimated incidence between. 1 in 16,000 and 1 in 18,000 live births [1] Rb occurs in both heritable (25–30%) and nonheritable (70–75%) forms. A heritable form is defined by the presence of a germline heterozygotic variant in the RB1 gene (Genbank accession number L11910.1; NCBI RefSeq. NM_000321.2), which is followed by a second somatic hit in the developing retina. In the nonheritable form, both mutations occur in somatic cells, usually leading to unilateral malignancy [2]. Due to the genetic predisposition, second malignant neoplasias (SMN) may arise spontaneously or following radiotherapy. Osteosarcomas in retinoblastoma patients occurred 1.2 years earlier, and the latency period between radiotherapy and osteosarcoma onset was 1.3 years shorter inside the radiation field than outside it [5]
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