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What Is the Association Between Genotype, Phenotype in Patients With Retinoblastoma?

Gianna Melillo
Currently, retinoblastoma (RB) occurs in 1 of every 20,000 births, making it the most common pediatric intraocular neoplasm. The cancer results from biallelic inactivation of the RB1 tumor-suppressor gene, which encodes the nuclear phosphoprotein RB protein. 
Retinoblastoma (RB) risk is associated with the germline pathogenic variant and with maintenance of the RB protein, according to a study published in JAMA Opthalmology.

Currently, RB occurs in 1 of every 20,000 births, making it the most common pediatric intraocular neoplasm. The cancer results from biallelic inactivation of the RB1 tumor-suppressor gene, which encodes the nuclear phosphoprotein RB protein.

In nonhereditary RB, pathogenic variants of RB1 are somatic and occur in the same retinal cell, which develops into a tumor. However, in hereditary RB, the germline pathogenic variant of 1 allele is associated with RB, the study authors explain. “The germline pathogenic variant is either inherited from an affected parent or acquired during fetal development, whereas the second pathogenic variant on the other allele is somatic, usually acquired during early childhood.”

To determine the association between genotype and phenotype in patients with RB, the investigators conducted a single-center retrospective cohort study of 1404 consecutive unrelated individuals between January 2000 and September 2017. All patients with RB who consulted an oncogeneticist at the Institut Curie in France, and had their genotype and phenotype recorded, were included in the study

Along with RB1 germline and somatic pathogenic variant types, family history and disease presentation characteristics were also assessed. In total, 734 (52.3%) patients were female, and the average study participant age was 20.2 years. Of the 1404 cases of RB, 866 (61.7%) were unilateral and 538 (38.3%) were bilateral.

After excluding tumor-specific pathogenic variants (ie, promoter methylation and loss of heterozygosity), the researchers found loss of function variants throughout the coding sequence, “with 259 of 272 (95.2%) somatic pathogenic variants and 537 of 606 (88.6%) germline pathogenic variants (difference, 6.6%; 95% CI, 4.0%-9.2%; P <.001).”

Data revealed that compared with germline pathogenic variants estimated to retain RB protein expression, germline pathogenic variants estimated to abrogate RB protein expression were associated with the following measures:
  • An earlier mean (SD) age at diagnosis: 12.3 (11.3) months among 457 patients vs 16.3 (13.2) months among 55 patients (difference, 4 months; 95% CI, 1.9-6.1; P = .01])
  • More frequent bilateral involvement: 84.2% among 452 patients vs 65.2% among 45 patients (difference, 18.9%; 95% CI, 14.5%-23.3%; P <.001)
  • More advanced International Intraocular Retinoblastoma Classification group: 85.3% among 339 patients vs 73.9% among 34 patients (difference, 11.4%; 95% CI, 6.5%-16.3%; P = .047)
In addition, the researchers found among the 765 nongermline carriers of an RB1 pathogenic variant, most were female, suggesting a sex-linked mechanism for nongermline carriers. Males were also more likely to have bilateral RB.

“These data showed that tumor pathogenic variants have a more severe association with RB protein than germline pathogenic variants,” the authors conclude. “Our findings support RB protein maintenance and use of the RB1 gene as a candidate for exon skipping or read-through treatment strategies in the retina.”

Reference

Salviat F, Gauthier-Villars M, Carton M, et al. Association between genotype and phenotype in consecutive unrelated individuals with retinoblastoma. JAMA Ophthalmol. Published online June 18, 2020. doi:10.1001/jamaophthalmol.2020.2100

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