[Molecular diagnosis of retinoblastoma: molecular epidemiology and genetic counseling].
OBJECTIVE
Retinoblastoma, a prototype of hereditary cancer, is the most common intraocular tumor in children and a potential cause of blindness from therapeutic eye ablation, second tumors in germ line mutation carriers, and even death when untreated. The molecular scanning of RB1 in search of germ line mutations in 213 retinoblastoma patients from Spain, Cuba, Colombia and Serbia, has led to the detection of 106 mutations whose knowledge is important for genetic counselling and characterization of phenotypic-genotypic relations.


METHODS
Mutational study (PCR-sequentiation and microsatellites analysis) in patients with retinoblastoma, from Spain, Cuba, Colombia and Serbia.


RESULTS
45% of mutations, including most of the frame shift (FS), missense (MS) and splicing (SP), were new, while all nonsense mutations (NS) corresponded to hypermutable sites in RB1. Germ line mutations were found in 22% of unilateral sporadic patients. The incidence of SP plus MS mutations in this group of patients was greater (p = 0.018) than in bilateral patients. The frequency of SP mutations was higher (p = 0.0003) in Spain and France than in Germany and United Kingdom, while the incidence of NS mutations was lower (p = 0.0006). SP mutations were associated with the low penetrance phenotype and were also overrepresented (p = 0.018) in patients with delayed retinoblastoma onset.


CONCLUSIONS
Mutational scanning of unilateral patients is important for genetic counselling and may help decipher the molecular mechanisms leading to low penetrance or expressivity. The functional characterization of mutations associated with low-penetrance or expressivity phenotypes and the molecular classification of tumors using multiple expression profiling is important for a better understanding of the retinoblastoma pathogenesis.
Alonso
Javier
J
OncoLab, Departamento de Biología Molecular y Celular del Cáncer, Instituto de Investigaciones Biomédicas (IIB) Alberto Sols, CSIC-UAM, Madrid, Spain.
Palacios
Itziar
I
Gámez
Angelo
A
Camino
Isabel
I
Frayle
Helena
H
Menéndez
Ibis
I
Kontic
Milica
M
García-Miguel
Purificación
P
Sastre
Ana
A
Abelairas
José
J
Sarret
Enric
E
Sabado
Constantino
C
Navajas
Aurora
A
Artigas
Mercé
M
Indiano
José M
JM
Carbone
Ana
A
Rosell
Jordi
J
Pestaña
Angel
A
D002648:Child; D002675:Child, Preschool; D005260:Female; D005817:Genetic Counseling; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D012175:Retinoblastoma / Q000453:epidemiology* / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics*
D016160:Retinoblastoma Protein