Retinoblastoma (hereditary predisposition)

Predisposition to retinoblastoma is transmitted as an autosomal dominant trait trait with incomplete penetrance (Vogel F, 1979; Eloy P et al., 2016; Imperatore V et al., 2018);; it is caused by mutations in the RB1 gene; there is also a non-hereditary form of retinoblastoma (mostly in children with isolated unilateral retinoblastoma) that is caused by RB1-mutations confined to somatic cells

180200

D012175

790 Retinoblastoma

C0035335

Early childhood: formation of retinoblastomas NEOPLASTIC_RISK Adolescence and adulthood: tumors outside the eye (second primary neoplasms):

osteosarcoma,

melanoma,

brain tumours (pinealoma in particular some patients also show multiple benign tumours of adipose tissue (lipoma).

Tumor stage, localization\/size of the tumor, number of foci, presence of vitreous seeding and the age of the child can influence the treatment of RB. On the basis of these factors, therapeutic approaches can include focal cryotherapy, laser surgery, radiotherapy or chemotherapy. More recently, intra-arterial selective infusion of chemotherapy in the ophthalmic artery has been introduced (Peterson EC et al., 2011; Venturi C et al., 2013). However, enucleation (removal of the entire eye) is still the standard treatment for advanced intraocular RB, since it is effective in preventing progression to clinical metastatic disease in 95% of cases (Balmer A et al., 2006).
Surveillance: following the diagnosis of retinoblastoma, repeated examinations under general anesthesia are required for early diagnosis of new tumour foci; up to now, no screening for second primary neoplasms.

Most often, treatment of retinoblastoma is very effective and, therefore, death from retinoblastoma is rare; however, life span in patients that develop second primary neoplasms is reduced (cumulative mortality at age 40: 6.4% in bilateral patients without radiotherapy, 1.5% in patients with unilateral retinoblastoma).

Large-sized molecular deletions including RB1 have been found in 10% of cases causing a contiguous gene deletion syndrome characterized by retinoblastoma, developmental abnormalities and peculiar facial dysmorphisms such as cranial anomalies, frontal bossing, deeply grooved and long philtrum, depressed and broad nasal bridge, bulbous tip of the nose, thin upper lip, broad cheeks, and large ears and lobules (Kloss et al., 1991; Bojinova RI et al., 2001; Lohmann and Gallie 2004; Albrecht P et al., 2005; Caselli R et al., 2007). Few cases of complex translocations resulting in retinoblastoma are reported, and chromosomes involved of balanced reciprocal translocations with 13q14 include 1, 2, 18, 20, and X (Cross HE et al., 1977; Kajii T et al., 1985; Keith CG et al., 1985; Blanquet V et al., 1987; Trivino E et al., 1997; Laquis SJ et al., 2002; Dries D et al., 2003; Huddleston S et al., 2013).

p105-Rb

180 kb genomic DNA containing 27 exons

4.7 kb mRNA with 2.7 kb open reading frame

928 amino acids nuclear phosphoprotein.

In most tissues.

nucleus

Involved in cell cycle regulation, heterochromatin formation, maintenance of genome stability, regulation of cell differentiation and apoptosis (Dimaras H et al., 2015; Dyson NJ et al., 2016).

More than 1,700 different mutations, ranging from single nucleotide changes to large deletions, have been listed in the RB1 Gene Mutation Database (http:\/\/rb1-lovd.d-lohmann.de). A large fraction (~40%) of mutations are recurrent and consist in sixteen hot spots, including twelve nonsense, one missense and three splicing mutations (Valverde JR et al., 2005). Remaining mutations are scattered along the 27 exons, the promoter and intronic regions (splice site and deep intronic mutations). Complete inactivation of the protein is the result of the majority of RB1 mutations (complete loss of function, amorphic mutations). These mutations, mostly represented by nonsense and frameshift changes resulting in premature termination codons (PTC), are generally associated with full penetrance (Valverde JR et al., 2005). RB1 amorphic mutations can be associated to reduced penetrance in association with somatic mosaicism (Imperatore V et al., 2018). Hypomorphic mutations partially inactivating protein function or reducing gene expression combined with a parent-of-origin effect can also be associated to incomplete penetrance or variable expressivity (Kanber D et al., 2009; Eloy P et al., 2016; Imperatore V et al., 2018). Another important class of RB1 oncogenic events is represented by large rearrangements (~15%; Taylor M et al., 2007). They can include only the RB1 gene (entire or a portion) or be a part of a larger contiguous deletion involving other genes. Whole gene deletions are associated to the development of fewer tumors (Albrecht P, et al. 2005; Taylor M et al., 2007). A minimal genomic region associated with low penetrance has been defined and MED4 has been identified as a gene fundamental for the survival of RB1-\/- tumor cells (Dehainault C et al., 2014).

In the majority of retinoblastoma tissues, the mutations that result in biallelic inactivation of the RB1 gene are accompanied by loss of constitutional heterozygosity (LOH), originating from deletions and several chromosomal mechanisms such as mitotic recombination and nondisjunction (Cavenee WK et al., 1983; Zhu X et al., 1992; Hagstrom SA and Dryja TP, 1999; Lohmann DR et al., 1997). RB1 promoter hypermethylation is observed in about 13% of retinoblastomas (Greger V et al., 1994; Ohtani-Fujita N et al., 1997; Klutz M et al., 1999).

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http:\/\/home.kamp.net\/home\/dr.lohmann\/index.htm Database of RB1-gene mutations