MUTATIONS IN THE RB1 GENE IN RETINOBLASTOMA PATIENTS AND THEIR CLINICAL CORRELATION

PARMA DIANA; LUCE LEONELA; FERRER M. ;; FLORENCIA GILIBERTO,; , SZIJAN IRENE

Mar del PLata

Congreso; LXI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC) LXIV REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INMUNOLOGÍA (SAI) XLVIII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE FARMACOLOGÍA EXPERIMENTAL (SAFE); 2016

SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC)

Mutations in the RB1 gene in retinoblastoma patients and their clinical correlation.Parma Diana, Luce Leonela, Ferrer Marcela, Giliberto Florencia and Szijan Irene Retinoblastoma; Clinical presentation; RB1 tumor suppressor gene; RB1 mutations; Genotype-Phenotype correlationRetinoblastoma (RB) is a hereditary cancer of childhood caused by mutations in the RB1 tumor suppressor gene. An early diagnosis is critical for survival and eye preservation, thus identification of mutations is important for unequivocal diagnosis and risk assessment in relatives. Unilateral RB is mostly non-hereditary, carrying somatic mutations, while bilateral RB is always hereditary carrying germline mutations. The purpose of this work was to identify the causative mutations in RB patients with different clinical presentations. A comprehensive approach was used to detect children with a hereditary condition. A cohort of 22 patients with unilateral, bilateral and trilateral RB was studied. Blood and tumor DNA was analyzed by sequencing and MLPA analyses. Four out of 16 unilateral RB carried mutations in blood DNA, two patients with missense mutations, transmitted by one of the parents, one with nonsense and other with a frameshift mutation. Five out of six bilateral and trilateral RB carried splice site, nonsense and frameshift mutations as well as a whole RB1 gene deletion. All but one nonsense/frameshift germline mutations were associated with severe phenotype: bilateral, trilateral or a unilateral RB with an early tumor development. One nonsense germline mutation was identified in a unilateral patient with a late diagnosis, however the amount of mutated copy was smaller than the normal one (40%) suggesting somatic mosaicism. Missense mutations were associated with a mild phenotype: unilateral RB, retinoma or no tumor. Analysis of tumor DNA identified mutations in both RB1 copies in two patients, which were not present in blood DNA, revealing a nonhereditary nature of RB. This study allowed us to identify causative RB1 mutations, including several novels. These data are significant for genetic counseling and support the relevance of carrying out complete genetic screening for RB1 mutations in both constitutional and tumor tissues.