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      Retinoblastoma in twins: Risk assessment of genotypic variants

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          Abstract

          Purpose:

          To describe methods of risk assessment in twins with retinoblastoma (RB).

          Methods:

          A case series of four RB probands with a twin sibling. Family status, clinical presentation, and RB1 germline status-based risk assessment were analyzed.

          Results:

          Two pairs had a positive family history (unilateral and bilateral RB in one of the parents (#1 and #2, respectively) and two pairs (#3 and #4) were sporadic. One of the familial twins (#1) had a high risk (90%) of manifesting RB in the twin. The other case (#2) with an absent RB1 germline mutation in the twin had a 0% risk of developing RB. Among sporadic cases of twins (#3), genetic testing did not identify a germline mutation (tumor sample unavailable) in the proband which downgraded the risk of germline mutation from 15% to <1%. The twin never developed RB (5 years of age at last follow-up). Pathogenic mosaicism for germline RB1 mutation (c.1723C>T) could be identified (tumor tissue available) in the proband (# 4). Identical germline mutation (and RB tumor) was also noted in the twin. In each case, there was concordance between the assessed risk and manifestation of RB.

          Conclusion:

          Assessment of risk of RB in a twin presents with a unique challenge. Depending upon the genotype variant, the risk of developing RB can vary from 0% to 90%. In addition to family history, clinical manifestation in the proband, zygosity status, and RB1 germline status are critical in formulating risk-appropriate surveillance guidelines.

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          Most cited references29

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          Mutation and cancer: statistical study of retinoblastoma.

          A Knudson (1971)
          Based upon observations on 48 cases of retinoblastoma and published reports, the hypothesis is developed that retinoblastoma is a cancer caused by two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells. The second mutation produces an average of three retinoblastomas per individual inheriting the first mutation. Using Poisson statistics, one can calculate that this number (three) can explain the occasional gene carrier who gets no tumor, those who develop only unilateral tumors, and those who develop bilateral tumors, as well as explaining instances of multiple tumors in one eye. This value for the mean number of tumors occurring in genetic carriers may be used to estimate the mutation rate for each mutation. The germinal and somatic rates for the first, and the somatic rate for the second, mutation, are approximately equal. The germinal mutation may arise in some instances from a delayed mutation.
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            The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death.

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              Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies.

              Retinoblastoma is the childhood retinal cancer that defined tumour-suppressor genes. Previous work shows that mutation of both alleles of the RB1 retinoblastoma suppressor gene initiates disease. We aimed to characterise non-familial retinoblastoma tumours with no detectable RB1 mutations. Of 1068 unilateral non-familial retinoblastoma tumours, we compared those with no evidence of RB1 mutations (RB1(+/+)) with tumours carrying a mutation in both alleles (RB1(-/-)). We analysed genomic copy number, RB1 gene expression and protein function, retinal gene expression, histological features, and clinical data. No RB1 mutations (RB1(+/+)) were reported in 29 (2·7%) of 1068 unilateral retinoblastoma tumours. 15 of the 29 RB1(+/+) tumours had high-level MYCN oncogene amplification (28-121 copies; RB1(+/+)MYCN(A)), whereas none of 93 RB1(-/-) primary tumours tested showed MYCN amplification (p<0·0001). RB1(+/+)MYCN(A) tumours expressed functional RB1 protein, had fewer overall genomic copy-number changes in genes characteristic of retinoblastoma than did RB1(-/-) tumours, and showed distinct aggressive histological features. MYCN amplification was the sole copy-number change in one RB1(+/+)MYCN(A) retinoblastoma. One additional MYCN(A) tumour was discovered after the initial frequencies were determined, and this is included in further analyses. Median age at diagnosis of the 17 children with RB1(+/+)MYCN(A) tumours was 4·5 months (IQR 3·5-10), compared with 24 months (15-37) for 79 children with non-familial unilateral RB1(-/-) retinoblastoma. Amplification of the MYCN oncogene might initiate retinoblastoma in the presence of non-mutated RB1 genes. These unilateral RB1(+/+)MYCN(A) retinoblastomas are characterised by distinct histological features, only a few of the genomic copy-number changes that are characteristic of retinoblastoma, and very early age of diagnosis. National Cancer Institute-National Institutes of Health, Canadian Institutes of Health Research, German Research Foundation, Canadian Retinoblastoma Society, Hyland Foundation, Toronto Netralaya and Doctors Lions Clubs, Ontario Ministry of Health and Long Term Care, UK-Essen, and Foundations Avanti-STR and KiKa. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Indian J Ophthalmol
                Indian J Ophthalmol
                IJO
                Indian Journal of Ophthalmology
                Wolters Kluwer - Medknow (India )
                0301-4738
                1998-3689
                May 2021
                30 April 2021
                : 69
                : 5
                : 1230-1233
                Affiliations
                [1]Department of Ocular Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA
                [1 ]Department of Genetics, Cleveland Clinic, Cleveland, Ohio, USA
                Author notes
                Correspondence to: Dr. Arun Singh, Department of Ocular Oncology, Cole Eye Institute, Cleveland Clinic Foundation, Ohio, USA. E-mail: singha@ 123456ccf.org
                Article
                IJO-69-1230
                10.4103/ijo.IJO_2811_20
                8186642
                33913866
                114422be-41fa-48de-81ce-2afa029309fe
                Copyright: © 2021 Indian Journal of Ophthalmology

                This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

                History
                : 01 September 2020
                : 04 December 2020
                : 10 December 2020
                Categories
                Original Article

                Ophthalmology & Optometry
                genetic testing,germline,mosaic,retinoblastoma,twins
                Ophthalmology & Optometry
                genetic testing, germline, mosaic, retinoblastoma, twins

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