Purchase this article with an account.
Leen Abu Safieh, Saleh Al-Mesfer, Maha W Othman, Mohammed Karaoui, Hind Al Katan, Deepak Edward; Novel Mutations in the RB1 Gene in Retinoblastoma patients with treatment failure. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6441.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Retinoblastoma (Rb) is initiated by the biallelic loss of RB1. Rb treatment is multimodal and often successful. However, treatment failures do occur resulting in enucleation. We hypothesized that specific mutation in RB1 may contribute to treatment failure.
Two children with Rb with treatment failure with multiple treatment modalities were studied. Clinical findings, pathologic features following enucleation and treatment were documented. DNA was extracted from harvested fresh tumor, adjacent normal tissue and blood from patients and relatives. Mutation analysis was done by direct sequencing of all RB1 exons and flanking regions. The presumed impact of variants on the structure of the Rb protein was predicted by Polymorphism Phenotyping-2 and mutation taster. Polymorphism analysis was used to determine loss of heterozygosity in tumour samples. Germline mutations were excluded from being rare population polymorphism by sequencing 288 DNA samples extracted from Saudi normal controls blood.
Patient 1, a 17 month old male presented with unilateral sporadic group D Rb. After 6 cycles of chemo and radiotherapy, the patient developed recurrent active tumor. Pathologic examination showed vitreous seeding, viable intraocular tumor without high risk features. Patient 2 was a 13 month boy with sporadic bilateral Rb, right eye (enucleated) & group D, left eye. The left eye received 9 cycles of chemo and radiotherapy but progressed to stage E resulting in enucleation. Pathology showed viable intraocular tumor, focal choroidal invasion and optic nerve invasion with negative surgical margin. We identified two novel truncation mutations in the RB1 gene. In patient 1, an insertion of two base pairs was identified that resulted in a frameshift and protein truncation (c.282_283insAA). Patient 2 showed a stop mutation early in the protein sequence (c.103C>T, p: Q35*). Both mutations were identified as germline and somatic mutation.
Here we report two novel germline and somatic mutations in the RB1 gene. These novel mutations in patients with advanced Rb resulted in poor ocular survival despite extensive multimodal treatment. Nonsense mutations, insertions and deletions represent over 50% of all RB1mutations. It is possible that this type of mutations responsible for tumor resistance to treatment. Screening additional patients with similar clinical history is required to confirm such conclusion.
This PDF is available to Subscribers Only