Genetics in ophthalmology: molecular blueprints of retinoblastoma

Abstract

This review presents current knowledge on the molecular biology of retinoblastoma (RB). Retinoblastoma is an intraocular tumor with hereditary and sporadic forms. 8,000 new cases of this ocular malignancy of the developing retina are diagnosed each year worldwide. The major gene responsible for retinoblastoma is RB1, and it harbors a large spectrum of pathogenic variants. Tumorigenesis begins with mutations that cause RB1 biallelic inactivation preventing the production of functional pRB proteins. Depending on the type of mutation the penetrance of RB is different. However, in small percent of tumors additional genes may be required, such as MYCN, BCOR and CREBBP. Additionally, epigenetic changes contribute to the progression of retinoblastoma as well. Besides its role in the cell cycle, pRB plays many additional roles, it regulates the nucleosome structure, participates in apoptosis, DNA replication, cellular senescence, differentiation, DNA repair and angiogenesis. Notably, pRB has an important role as a modulator of chromatin remodeling. In recent years high-throughput techniques are becoming essential for credible biomarker identification and patient management improvement. In spite of remarkable advances in retinoblastoma therapy, primarily in high-income countries, our understanding of retinoblastoma and its specific genetics still needs further clarification in order to predict the course of this disease and improve therapy. One such approach is the tumor free DNA that can be obtained from the anterior segment of the eye and be useful in diagnostics and prognostics.

Genetic Risk Factors and Clinical Outcomes in Childhood Eye Cancers: A Review

“…By contrast, non-heritable RB arises from two somatic mutations of the RB1 gene acquired during retinal development [ 29 ]. While most hereditary cases of RB are bilateral, approximately 10% to 15% of children with unilateral RB are inherited in an autosomal dominant manner [ 14 , 30 ]. Around 80% of cases show no family history and harbor de novo germline mutations [ 14 , 30 ].…”

“…While most hereditary cases of RB are bilateral, approximately 10% to 15% of children with unilateral RB are inherited in an autosomal dominant manner [ 14 , 30 ]. Around 80% of cases show no family history and harbor de novo germline mutations [ 14 , 30 ]. Children with hereditary RB or those carrying a single copy of a mutated RB1 gene have an elevated risk of developing multiple retinoblastomas in both eyes during their early life.…”

“…Children with hereditary RB or those carrying a single copy of a mutated RB1 gene have an elevated risk of developing multiple retinoblastomas in both eyes during their early life. Moreover, they have a lifelong risk of developing non-ocular malignancies such as osteosarcomas, soft tissue sarcomas, and melanomas [ 6 , 30 ].…”

“…Thus, mutations in pRB lead to disruption of cell cycle regulation and uncontrolled cell division, causing retinoblastoma tumor development [ 13 , 15 , 29 ]. Retinoblastoma is linked to a wide variety of RB1 gene pathogenic mutations [ 29 , 30 ]. In hereditary RB, nonsense (37%) or frameshift (20%) mutations within exons 2 to 25 are the most common mutations that result in the loss or inactivation of the RB1 gene [ 27 , 29 , 30 ].…”

“…Retinoblastoma is linked to a wide variety of RB1 gene pathogenic mutations [ 29 , 30 ]. In hereditary RB, nonsense (37%) or frameshift (20%) mutations within exons 2 to 25 are the most common mutations that result in the loss or inactivation of the RB1 gene [ 27 , 29 , 30 ]. Other types of pathogenic variations that have been found to disturb the function of the RB1 gene include point mutations, chromosomal rearrangements, large exonic deletions, and the hypermethylation of the gene promoter region [ 27 , 29 , 30 ].…”