Abstract
Retinoblastoma (Rb), the most common pediatric intraocular neoplasm, results from inactivation of both alleles of the RB1 tumor suppressor gene. The second allele is most commonly lost, as demonstrated by loss of heterozygosity studies. RB1 germline carriers usually develop bilateral tumors, but some Rb families display low penetrance and variable expressivity. In order to decipher the underlying mechanisms, 23 unrelated low penetrance pedigrees segregating the common c.1981C>T/p.Arg661Trp mutation and other low penetrance mutations were studied. In families segregating the c.1981C>T mutation, we demonstrated, for the first time, a correlation between the gender of the transmitting carrier and penetrance, as evidenced by Fisher’s exact test: the probability of being unaffected is 90.3% and 32.5% when the mutation is inherited from the mother and the father, respectively (p-value = 7.10−7). Interestingly, a similar correlation was observed in families segregating other low penetrance alleles. Consequently, we investigated the putative involvement of an imprinted, modifier gene in low penetrance Rb. We first ruled out a MED4-driven mechanism by MED4 methylation and expression analyses. We then focused on the differentially methylated CpG85 island located in intron 2 of RB1 and showing parent-of-origin-specific DNA methylation. This differential methylation promotes expression of the maternal c.1981C>T allele. We propose that the maternally inherited c.1981C>T/p.Arg661Trp allele retains sufficient tumor suppressor activity to prevent retinoblastoma development. In contrast, when the mutation is paternally transmitted, the low residual activity would mimic a null mutation and subsequently lead to retinoblastoma. This implies that the c.1981C>T mutation is not deleterious per se but needs to be destabilized in order to reach pRb haploinsufficiency and initiate tumorigenesis. We suggest that this phenomenon might be a general mechanism to explain phenotypic differences in low penetrance Rb families.
Highlights
Retinoblastoma (Rb) is the most common pediatric intraocular neoplasm and occurs in 1 of every 15,000 births
Complex genotype-phenotype correlations lead to clinically and emotionally difficult situations. Improved understanding of these correlations is of utmost importance in medical genetics
Eight low penetrance families derived from the literature were found by PubMed search and were added to the study (Table 1)
Summary
Retinoblastoma (Rb) is the most common pediatric intraocular neoplasm and occurs in 1 of every 15,000 births. It results from the biallelic inactivation of the RB1 tumor suppressor gene, located on 13q14 [1]. RB1 encodes the nuclear phosphoprotein pRB, which plays a prominent role during the G1/S phase transition[2]. In tumors, both RB1 alleles can be inactivated via diverse mechanisms including point mutations, large rearrangements, promoter hypermethylation and, most frequently, loss of the second allele demonstrated by loss of heterozygosity studies. Non-hereditary retinoblastomas are usually unilateral (one eye affected) with a median age at diagnosis of 2 years, whereas hereditary cases are usually bilateral (both eyes affected) with a median age at diagnosis of 1 year and an increased risk for second tumors
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