CONICET | Buscador de Institutos y Recursos Humanos

Retinoblastoma (RB) is a hereditary cancer of childhood causedby mutations in RB1 tumor suppressor gene. An early diagnosis iscritical for survival and eye preservation, thus identification of mutationsis important for unequivocal diagnosis and risk assessment inrelatives. Unilateral RB is non-hereditary in 80% of cases, while approximately20% of unilateral RB is hereditary. These patients haveseveral risks: bilateralization of retinoblastoma, development of othertumors in adulthood and transmission of the RB predisposition totheir offspring. The purpose of this work was to identify the causativemutations in two unilateral RB patients with different clinical presentations.One of them (#686) was diagnosed at 1 month and the other(#689) at 4 years, both were enucleated. DNA was extracted fromblood and tumor and analyzed by sequence and MLPA assays.Analysis of tumor DNA identified mutations in both RB1 copies inthe two patients, which were thereafter sought in blood. Tumor DNAof patient #686 displayed a T duplication in exon 14, which was alsopresent in blood DNA; thus, this was the first RB1 mutation and itwas germline. The second mutation in tumor (the somatic one) wasa deletion of RB1 exons 1 and 2 plus a centromeric gene (ITM2B5).Both were frameshift novel mutations Tumor DNA of patient #689showed an A duplication in exon 2 as a first frameshift RB1 mutationand a loss of a wild type chromosome 13 (without reduplication ofthe mutant chromosome) as a second mutation. None of the twomutations were found in blood, thus, they were somatic. These resultsreveal a hereditary nature of mutations in the patient #686,with an early diagnosis, and a nonhereditary nature of mutationsin patient #689, with a late diagnosis. These data are significant forgenetic counseling and support the relevance of carrying out completegenetic screening for RB1 mutations in both constitutional andtumor tissues.

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