Abstract

P 093

Spectrum of germline RB1 gene mutations in Serbian retinoblastoma patients

Kontic M.¹, Kontic M.¹, Palacios I.², Alonso J.², Pestana A.^2
1Institute for Pulmonary Diseases, Clinical Center of Serbia, School of Medicine, Belgrade, Serbia; ²Clinic for Eye Diseases, Military Medical Academy, Belgrade, Serbia; Oncolab, Instituto de Investigaciones Biomedicas “Alberto Sols”, Madrid, Espana

Objective: Contemporary research in molecular genetics made a great contribution in prevention, early diagnosis and prognosis of retinoblastoma. Gene responsible for retinoblastoma, RB1 gene, is the prototype of the tumor suppressor gene. Two mutational events are required for the initiation of retinoblastoma. Modern methods of molecular genetics allowed detection of large number of mutations on DNA isolated from peripheral blood, and from DNA isolated from tumors of retinoblastoma patients. Ability to detect mutations in RB1 gene is the base for studying the genetics of retinoblastoma and determining prenatal risk for developing this kind of tumor. Aim of this research was detection of germline RB1 mutations in 16 Serbian retinoblastoma patients, as well as 22 of their parents, for genetic counseling. This is the first molecular genetic research in Serbian retinoblastoma patients.
Methods: The mutational studies were carried out in the peripheral blood DNA of 4 bilateral and 12 unilateral retinoblastoma patients and 22 of their parents, referred to the Institute of Ophthalmology, Belgrade, Serbia. DNA was extracted from all samples and mutation analysis was carried out by PCR directed sequencing of the 27 exons. All mutations and polymorphisms detected were confirmed by duplicate sequence analysis in both directions from separated PCR reactions.
Results: In the course of this study we have found seven small length RB1 mutations. Among them there are five new RB1 oncogenic mutations (g.2078delC, g.77047_48delGC, g.78117_8delTT, g.160797delT, and g.64439+2T>C), never reported before, as well as two recurrent mutations (R445X, Q383X). In addition, four intronic variants were observed germline in some unilateral patients. Two of these variants are discussed as potential oncogenic mutation candidates. Retinoblastoma patients and their parents who have germline RB1 mutation are carriers of retinoblastoma through family. There is 45% (due to penetrance) risk for their offspring and siblings to be affected by retinoblastoma.
Conclusions: The identification of germline mutations is important to detect affected or asymptomatic carriers within a pedigree, and also to provide prenatal or preimplantation genetic diagnosis. In this study, the oncogenic mutation detected in the patient with family history was also found germline in the affected father, but not in chorionic villi of the pregnant mother, within a prenatal diagnosis of fetus in one Serbian retinoblastoma family. Knowledge of the individual RB1 mutation affords an opportunity for accurate risk prediction in relatives of patients with retinoblastoma.

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