A Parent-of-Origin Effect Impacts the Phenotype in Low Penetrance Retinoblastoma Families Segregating the c.1981C>T/p.Arg661Trp Mutation of RB1

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.

Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity”

“…The minor allele of rs2279744 (NM_001145337.2:c.-291T > G), a single-nucleotide polymorphism in the MDM2 promoter known to be linked to enhanced MDM2 expression, has been reported to act as a modifier of phenotypic expression in heritable retinoblastoma (Castera et al, 2010). Parent-oforigin effects have been identified as another source of intra-familial variation of phenotypic expression (Klutz et al, 2002), found later to be related to human RB1 gene imprinting (Eloy et al, 2016;Kanber et al, 2009).…”

Parent-of-origin effect of hypomorphic pathogenic variants and somatic mosaicism impact on phenotypic expression of retinoblastoma

“…However, it is common to observe families in which a significant fraction of pathogenic variant carriers remains unaffected or develops only unilateral tumors or benign lesions called retinomas [5], a phenomenon that has always posed a question about the underlying mechanisms. Pathogenic variants reducing RB1 expression or partially inactivating pRB activity have been associated to milder phenotypic expression [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. However, the description of low-penetrant families bearing classical "null" variants and the observation that penetrance/expressivity can vary significantly between and within families with identical pathogenic variants has led to speculate that other mechanisms may be determinant [17,[21][22][23][24].…”

Osteosarcoma without prior retinoblastoma related to RB1 low‐penetrance germline pathogenic variants: A novel type of RB1‐related hereditary predisposition syndrome?

“…Interestingly, all individuals diagnosed with first primary sarcoma carried RB1 low‐penetrance alleles. Hence, we questioned if the parent of origin effect demonstrating a higher Rb risk with paternally inherited low‐penetrance alleles holds true with sarcoma risk (Eloy et al, ). A paternal inheritance was observed (3 out of 3 cases) in families with p.Arg661Trp carriers affected by first primary sarcoma or melanoma without prior Rb (Dommering et al, , family S1B, family S1D) but the number of families is too small to draw any conclusion.…”