Introduction of a Variant Classification System for Analysis of Genotype-Phenotype Relationships in Heritable Retinoblastoma

Abstract

Constitutional haploinsufficiency of the RB1 gene causes heritable retinoblastoma, a tumor predisposition syndrome. Patients with heritable retinoblastoma develop multiple retinoblastomas early in childhood and other extraocular tumors later in life. Constitutional pathogenic variants in RB1 are heterogeneous, and a few genotype-phenotype correlations have been described. To identify further genotype-phenotype relationships, we developed the retinoblastoma variant effect classification (REC), which considers each variant’s predicted effects on the common causal mediator, RB1 protein pRB. For validation, the RB1 variants of 287 patients were grouped according to REC. Multiple aspects of phenotypic expression were analyzed, known genotype-phenotype associations were revised, and new relationships were explored. Phenotypic expression of patients with REC-I, -II, and -III was distinct. Remarkably, the phenotype of patients with variants causing residual amounts of truncated pRB (REC-I) was more severe than patients with complete loss of RB1 (REC-II). The age of diagnosis of REC-I variants appeared to be distinct depending on truncation’s localization relative to pRB structure domains. REC classes identify genotype-phenotype relationships and, therefore, this classification framework may serve as a tool to develop tailored tumor screening programs depending on the type of RB1 variant.

Germline RB1 Mutation in Retinoblastoma Patients: Detection Methods and Implication in Tumor Focality

“…Of note, mutations in exons 8 and 23, encoding the linkers connecting structured regions of the RB protein, are strongly associated with the development of bilateral RB and early patient age and are thus considered “hotspots” for patients with bilateral RB. 24 , 25 Additionally, a mutation in exon 18, encoding the linker connecting pockets A and B, is also often found in heritable RB 24 and was found in our cohort. The exons encoding the A/B structured domain and linkers of the RB protein represent a “hotspot” where a germline mutation is frequently identified.…”

Special Issue of Cancers: “Retinoblastoma: Current Challenges and Promising New Approaches”

“… The differential diagnosis of pediatric intra-ocular tumors and/or pseudo-tumors (a) in a multicenter prospective observational study of all new diagnoses of pediatric eye tumors over a 5-year period [ 8 ], and (b) through the use of magnetic resonance imaging (MRI) features that best differentiate between retinoblastoma and the most common pseudo-retinoblastoma diagnoses [ 9 ]. Novel genotype–phenotype correlations by means of a new classification for RB1 mutations, based on variants’ predicted effect on pRB, notably resulting in the hypothesis that truncated pRB could have a dominant-negative effect on wild-type pRB in a localization-dependent manner [ 10 ]. The occurrence of second non-ocular benign [ 11 ] and malignant [ 12 ] primaries in two large cohorts of retinoblastoma survivors.…”

“…Novel genotype–phenotype correlations by means of a new classification for RB1 mutations, based on variants’ predicted effect on pRB, notably resulting in the hypothesis that truncated pRB could have a dominant-negative effect on wild-type pRB in a localization-dependent manner [ 10 ].…”