Novel germline RB1 and MET gene mutations in a case with bilateral
retinoblastoma followed by multiple metastatic osteosarcoma
Abstract
Background 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 related with second primary malignancies arising
de novo, or following radiotherapy which have become the leading cause
of death in retinoblastoma survivors. Procedure We describe a
retinoblastoma case with a novel RB1 and a synchronous MET aberration.
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 uniqe form of
retinoblastoma. Results In this study we detected a retinoblastoma case
of non-parental origin with a novel RB1
c.2548C>T;p.(Gln850Ter) and a synchronous MET
c.3029C>T;p.(Thr1010Ile) germline mutations. Following
bilateral retinoblastoma the boy further developed at least four
different manifestations of two independent osteosarcomas. 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). Conclusions Because of the
expanding number of registered Rb cases, the novel rare cases
publication is very important to understand the molecular mechanism of
this malignancy. We reported a novel form of Rb and consequential
chondroblastic and osteoblastic osteosarcoma, the latter one developing
pulmonary metastatses.