Retinoblastoma Genetics Screening and Clinical Management

Overview

Journal BMC Med Genomics

Publisher Biomed Central

Specialty Genetics

Date 2021 Jul 23

PMID 34294096

Citations 6

Authors

Himika Gupta

Sivasankar Malaichamy

Ashwin Mallipatna

Sakthivel Murugan

Nallathambi Jeyabalan

Vishnu Suresh Babu

Anuprita Ghosh

Arkasubhra Ghosh

Sam Santhosh

Somasekar Seshagiri

Vedam L Ramprasad

Govindasamy Kumaramanickavel

Affiliations

Soon will be listed here.

Abstract

Background: India accounts for 20% of the global retinoblastoma (RB) burden. However, the existing data on RB1 gene germline mutations and its influence on clinical decisions is minimally explored.

Methods: Fifty children with RB underwent complete clinical examination and appropriate multidisciplinary management. Screening of germline RB1 gene mutations was performed through next-generation sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) analysis. The mutation and non-mutation groups were compared for clinical parameters especially severity, progression and recurrence.

Results: Twenty-nine patients had bilateral RB (BLRB) and 21 had unilateral RB (ULRB). The genetic analysis revealed 20 RB1 variations in 29 probands, inclusive of 3 novel mutations, known 16 mutations and heterozygous whole gene deletions. The mutation detection rate (MDR) was 86.2% in BLRB and 19% in ULRB. Associations of disease recurrence (p = 0.021), progression (p = 0.000) and higher percentage of optic nerve invasion, subretinal seeds and high-risk pathological factors were observed in the mutation group. Clinical management was influenced by the presence of germline mutations, particularly while deciding on enucleation, frequency of periodic follow up and radiotherapy.

Conclusions: We identified novel RB1 mutations, and our mutation detection rate was on par with the previous global studies. In our study, genetic results influenced clinical management and we suggest that it should be an essential and integral component of RB-care in India and elsewhere.

Citing Articles

Mutational analysis of the gene in patients with unilateral retinoblastoma.

Yousef Y, Mohammad M, Baqain L, Al-Hussaini M, Abu Shanap M, Halalsheh H Front Med (Lausanne). 2024; 11:1406215.

PMID: 39234041 PMC: 11371786. DOI: 10.3389/fmed.2024.1406215.

RB1 screening of retinoblastoma patients in Sri Lanka using targeted next generation sequencing (NGS) and gene ratio analysis copy enumeration PCR (GRACE-PCR).

Kugalingam N, Silva D, Abeysekera H, Nanayakkara S, Tirimanne S, Ranaweera D BMC Med Genomics. 2023; 16(1):279.

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The clinical diagnostic value of plasma miR-592 and miR-217-3p levels in retinoblastoma.

Yan L, Lin H, Yu H, Jie L, Chen J, Mei Y J Med Biochem. 2022; 41(4):497-505.

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Enhanced Epithelial-to-Mesenchymal Transition and Chemoresistance in Advanced Retinoblastoma Tumors Is Driven by miR-181a.

Babu V, Bisht A, Mallipatna A, Sa D, Dudeja G, Kannan R Cancers (Basel). 2022; 14(20).

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Advancing precision medicines for ocular disorders: Diagnostic genomics to tailored therapies.

Panikker P, Roy S, Ghosh A, Poornachandra B, Ghosh A Front Med (Lausanne). 2022; 9:906482.

PMID: 35911417 PMC: 9334564. DOI: 10.3389/fmed.2022.906482.

References

Kalsoom S, Wasim M, Afzal S, Shahzad M, Ramzan S, Awan A . Alterations in the RB1 gene in Pakistani patients with retinoblastoma using direct sequencing analysis. Mol Vis. 2015; 21:1085-92. PMC: 4575903. View

Joseph B, Raman R, Uthra S, Jagadeesan M, Ganesh A, Paul P . Genotype-phenotype correlation analysis in retinoblastoma patients from India. Asian Pac J Cancer Prev. 2007; 7(4):619-22. View

Ottaviani D, Parma D, Giliberto F, Ferrer M, Fandino A, Davila M . Spectrum of RB1 mutations in argentine patients: 20-years experience in the molecular diagnosis of retinoblastoma. Ophthalmic Genet. 2013; 34(4):189-98. DOI: 10.3109/13816810.2012.755553. View

Dommering C, Mol B, Moll A, Burton M, Cloos J, Dorsman J . RB1 mutation spectrum in a comprehensive nationwide cohort of retinoblastoma patients. J Med Genet. 2014; 51(6):366-74. DOI: 10.1136/jmedgenet-2014-102264. View

Khalid M, Yakob Y, Md Yasin R, Teik K, Siew C, Rahmat J . Spectrum of germ-line RB1 gene mutations in Malaysian patients with retinoblastoma. Mol Vis. 2015; 21:1185-90. PMC: 4605750. View

Stenson P, Mort M, Ball E, Howells K, Phillips A, Thomas N . The Human Gene Mutation Database: 2008 update. Genome Med. 2009; 1(1):13. PMC: 2651586. DOI: 10.1186/gm13. View

Price E, Price K, Kolkiewicz K, Hack S, Reddy M, Hungerford J . Spectrum of RB1 mutations identified in 403 retinoblastoma patients. J Med Genet. 2013; 51(3):208-14. DOI: 10.1136/jmedgenet-2013-101821. View

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N . The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-9. PMC: 2723002. DOI: 10.1093/bioinformatics/btp352. View

Mohammed A, Kamel A, Hammad S, Afifi H, El Sanabary Z, El Din M . Constitutional retinoblastoma gene deletion in Egyptian patients. World J Pediatr. 2009; 5(3):222-5. DOI: 10.1007/s12519-009-0042-1. View

10.

Zhang L, Jia R, Zhao J, Fan J, Zhou Y, Han B . Novel mutations in the RB1 gene from Chinese families with a history of retinoblastoma. Tumour Biol. 2014; 36(4):2409-20. DOI: 10.1007/s13277-014-2851-7. View

11.

Chen Z, Moran K, Richards-Yutz J, Toorens E, Gerhart D, Ganguly T . Enhanced sensitivity for detection of low-level germline mosaic RB1 mutations in sporadic retinoblastoma cases using deep semiconductor sequencing. Hum Mutat. 2013; 35(3):384-91. PMC: 4112364. DOI: 10.1002/humu.22488. View

12.

Mottaz A, David F, Veuthey A, Yip Y . Easy retrieval of single amino-acid polymorphisms and phenotype information using SwissVar. Bioinformatics. 2010; 26(6):851-2. PMC: 2832822. DOI: 10.1093/bioinformatics/btq028. View

13.

Afshar A, Pekmezci M, Bloomer M, Cadenas N, Stevers M, Banerjee A . Next-Generation Sequencing of Retinoblastoma Identifies Pathogenic Alterations beyond RB1 Inactivation That Correlate with Aggressive Histopathologic Features. Ophthalmology. 2020; 127(6):804-813. PMC: 7246167. DOI: 10.1016/j.ophtha.2019.12.005. View

14.

Seo S, Ahn H, Yu Y, Kang H, Park K, Cho S . Mutation spectrum of RB1 gene in Korean bilateral retinoblastoma patients using direct sequencing and gene dosage analysis. Clin Genet. 2012; 83(5):494-6. DOI: 10.1111/j.1399-0004.2012.01954.x. View

15.

Kunder R, Jalali R, Sridhar E, Moiyadi A, Goel N, Goel A . Real-time PCR assay based on the differential expression of microRNAs and protein-coding genes for molecular classification of formalin-fixed paraffin embedded medulloblastomas. Neuro Oncol. 2013; 15(12):1644-51. PMC: 3829591. DOI: 10.1093/neuonc/not123. View

16.

Tomar S, Sethi R, Sundar G, Quah T, Quah B, Lai P . Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling. PLoS One. 2017; 12(6):e0178776. PMC: 5456385. DOI: 10.1371/journal.pone.0178776. View

17.

. National Retinoblastoma Strategy Canadian Guidelines for Care: Stratégie thérapeutique du rétinoblastome guide clinique canadien. Can J Ophthalmol. 2010; 44 Suppl 2:S1-88. DOI: 10.3129/i09-194. View

18.

Grotta S, DElia G, Scavelli R, Genovese S, Surace C, Sirleto P . Advantages of a next generation sequencing targeted approach for the molecular diagnosis of retinoblastoma. BMC Cancer. 2015; 15:841. PMC: 4632486. DOI: 10.1186/s12885-015-1854-0. View

19.

Dommering C, Marees T, van der Hout A, Imhof S, Meijers-Heijboer H, Ringens P . RB1 mutations and second primary malignancies after hereditary retinoblastoma. Fam Cancer. 2011; 11(2):225-33. PMC: 3365233. DOI: 10.1007/s10689-011-9505-3. View

20.

Frenkel S, Zloto O, Sagi M, Fraenkel A, Peer J . Genotype-phenotype correlation in the presentation of retinoblastoma among 149 patients. Exp Eye Res. 2016; 146:313-317. DOI: 10.1016/j.exer.2016.04.002. View