Identification of novel RB1 genetic variants in Retinoblastoma patients and their impact on clinical outcome

ABSTRACT

Background

Retinoblastoma (RB) is an intraocular childhood cancer develops due to inactivation of RB1 gene. Identification of RB1 genetic variants, correlating and confirming genetic test results with clinical outcomes are crucial for effective RB management.

Methods

Retrospective study of 62 RB patients and 14 family members who underwent genetic testing either by next generation sequencing (NGS) or multiplex ligation-dependent probe amplification (MLPA) or by both for screening RB1 germline mutations present in peripheral blood. Mutational outcomes were correlated with clinical outcomes evaluated over a follow-up period of 12 months.

Results

Of the 62 patients, 35 (56%) had bilateral RB and 27 (44%) had unilateral RB. Out of 24 (52%) variants detected by NGS, 9 (37.5%) were novel and 15 (62.5%) were known in 46 probands. Six (18%) gross deletions were detected by MLPA in 34 probands. The mutation detection rate by NGS and MLPA in unilateral cases was 15% (n = 4) and 74% (n = 26) in bilateral cases. In patients with RB1 genetic mutations versus those without, the rate of primary enucleation (7 (12%) vs 18 (44%) eyes; p = .0008) was inversely proportional to tumor recurrence (25 (45%) vs 6 (15%) eyes; p = .002). There was no difference in the rate of globe salvage and metastasis, over a mean follow-up period of 12 months.

Conclusion

The mutations screening is important for risk assessment in future siblings and offspring of RB patients and most important in unilateral RB for determining if hereditary or not hereditary RB. Its role in predicting clinical outcomes is yet to be determined.

KEYWORDS:

• Retinoblastoma
• RB1 gene
• germline mutation
• genetic variants
• clinical outcome
• genetic testing
• tumor recurrence

Acknowledgments

The authors acknowledge the funding support from the Operation Eyesight Universal Institute for Eye cancer (SK) and Hyderabad Eye Research Foundation (SK), LV Prasad Eye Institute, Hyderabad, India

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethics approval statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and was approved by the Institutional Review Board of L V Prasad Eye Institute, Hyderabad, India − 500 034 (IRB approval no. LEC-BHR-01-20-390)

Authors contribution

The study was conceptualized by SK and RM. Data was collected and analyzed by RM, AP, GR. The manuscript is drafted by RM, AP, and SK. All the authors reviewed the manuscript and contributed with critical inputs to the final draft.

Additional information

Funding

The work was supported by Hyderabad Eye Research Foundation; and Operation Eyesight Universal Institute for Eye cancer.