Abstract
Purpose :
Genetic testing plays a critical role in determining the heritable nature of retinoblastoma (RB) and identifying the cancer risk for patients and their family members. This study aimed to describe the genotypic landscape of RB patients from North India and derive any genotype-phenotype correlations especially pertaining to aggressive disease.
Methods :
A Retrospective observational study was conducted including all RB patients who underwent genetic testing at a tertiary eye care hospital between January 2021 to December 2022. Whole exome sequencing (WES) targeting RB1 gene was performed on blood samples from the patients. When negative, Multiple Ligation Probe Analysis (MLPA) was performed to detect deletion/duplications in RB1 gene. The phenotype of the patients was determined based on the age of onset, disease severity (using the International Classification of Retinoblastoma and the International Retinoblastoma Staging System), metastasis status, globe salvage and tumor recurrence. Aggressive tumors were defined as those with age of onset <12 months, ICRB Groups C-E and tumor recurrence. The genetic variations were correlated with the phenotypic determinants.
Results :
Data from 150 RB patients (86 unilateral, 62 bilateral and 2 trilateral) was included in analysis. Positive family history of RB was seen in 11/150 (7.33%). 75/150 patients (50%; 58 bilateral, 17 unilateral) showed pathogenic genetic variations in RB1 gene. It was detected by WES in 69 cases (54 bilateral, 15 unilateral) and MLPA in 6 cases (4 bilateral, 2 unilateral). Point mutations were observed in 37/75 (49.3%), small deletions in 16/75 (21.33%), gene duplication in 3/75 (4%), large deletions in 8/75 (10.66%), splice site variations and promoter methylation 11/75 (14.66%). Non-sense variations and deletions in RB1 gene were the most frequently observed genetic variations and were also associated with aggressive disease. A unique clustering pattern of genetic variations was observed between exons 14-21 of RB1 gene in 50% of the patients.
Conclusions :
Exons 14-21 of the RB1 gene are a potential hotspot. Nonsense variations and deletions are associated with aggressive disease. The absence of RB1 mutations in half of the cases highlights the complex genomic landscape of RB that could be understood better by detailed analysis of somatic mutation profile of tumors.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.