Mutations in the RB1 gene in retinoblastoma patients and their clinical correlation

FERRER M; LUCE L; SZIJAN I; PARMA D; GILIBERTO F

Buenos Aires

Jornada; I Jornada de Divulgación de las Actividades del Departamento de Microbiología, Inmunología, Biotecnología y Genética de la Facultad de Farmacia y Bioquímica de la Universidad de Buenos Aires; 2018

Departamento de Microbiología, Inmunología, Biotecnología y Genética de la Facultad de Farmacia y Bioquímica de la Universidad de Buenos Aires

Retinoblastoma (RB) is ahereditary cancer of childhood caused by mutations in the RB1 tumorsuppressor gene. An early diagnosis is critical for survival and eyepreservation, thus identification of mutations is important for unequivocaldiagnosis and risk assessment in relatives. Unilateral RB is mostlynon-hereditary, carrying somatic mutations, while bilateral RB is always hereditary carrying germline mutations. The purpose of this work was toidentify the causative mutationsin RB patients with different clinical presentations. A comprehensive approachwas 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 16unilateral RB carried mutations in blood DNA, two patients with missensemutations, transmitted by one of the parents, one with nonsense and other witha frameshift mutation. Five out of six bilateral and trilateral RB carried splice site, nonsenseand frameshift mutations as well as a whole RB1 gene deletion. All butone nonsense/frameshift germline mutations were associated with severephenotype: bilateral, trilateral or aunilateral RB with an early tumor development. One nonsense germline mutationwas identified in a unilateral patient with a late diagnosis, however the amountof mutated copy was smaller than the normal one (40%) suggesting somaticmosaicism. Missense mutations were associated with a mild phenotype: unilateralRB, retinoma or no tumor. Analysis of tumor DNA identified mutations in both RB1copies in two patients, which were not present in blood DNA, revealing a nonhereditarynature of RB. This study allowed us to identify causative RB1 mutations,including several novels.