<i>RB1</i>mutation spectrum in a comprehensive nationwide cohort of retinoblastoma patients

Dommering, Charlotte J.; Mol, Berber M.; Moll, Annette C.; Burton, M.; Cloos, Jacqueline; Dorsman, Josephine C.; Meijers-Heijboer, Hanne; Hout, Annemarie H. van der

doi:10.1136/jmedgenet-2014-102264

Cited by 73 publications

(57 citation statements)

References 46 publications

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“…The frequency of heritable and non-heritable RB1 mutational events in this Singaporean cohort of 59 RB cases primarily comprised of familial or de novo sequence point mutations (50 cases), acquired intragenic and extragenic deletions (35 cases) and epigenetic changes (1 case). Although RB1 promoter hypermethylation has been observed to play an important role as one of the two hits in RB with varying frequencies ranging from 0–27% [49,51,55,59,60]; we found only one instance of this, concurring with the previous observation by Choy et al 2002, that it is not a major inactivating mechanism in our population which had a predominance of Chinese patients. The unilateral patient with promoter hypermethylation in our study also harboured a novel somatic upstream RB1 variant: c.-490A>T (Table 3 and S3 Table).…”

Section: Discussionsupporting

confidence: 91%

“…Thus, a combinatorial approach of RNA-based techniques and massive parallel sequencing is recommended for cases where no RB1 alteration can be identified. Nevertheless, our mutation detection rate of 92.5% for unilateral tumors and 100% for bilateral tumors, are comparable to other studies that have employed direct sequencing and MLPA as a combinatorial approach towards determining the RB1 mutational status with detection figures ranging between 92–100% for Bilateral and 10–61% in unilateral cases [45,50,55,70,71]. The high detection rates of RB1 gene mutations reported in our study shows that conventional techniques are still effective as clinical screening methods for most RB cases even in the era of next-generation sequencing due to the type of mutations that occur frequently in this disease.…”

Section: Discussionsupporting

confidence: 87%

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Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling

et al. 2017

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Retinoblastoma (RB) is a rare childhood malignant disorder caused by the biallelic inactivation of RB1 gene. Early diagnosis and identification of carriers of heritable RB1 mutations can improve disease outcome and management. In this study, mutational analysis was conducted on fifty-nine matched tumor and peripheral blood samples from 18 bilateral and 41 unilateral unrelated RB cases by a combinatorial approach of Multiplex Ligation-dependent Probe Amplification (MLPA) assay, deletion screening, direct sequencing, copy number gene dosage analysis and methylation assays. Screening of both blood and tumor samples yielded a mutation detection rate of 94.9% (56/59) while only 42.4% (25/59) of mutations were detected if blood samples alone were analyzed. Biallelic mutations were observed in 43/59 (72.9%) of tumors screened. There were 3 cases (5.1%) in which no mutations could be detected and germline mutations were detected in 19.5% (8/41) of unilateral cases. A total of 61 point mutations were identified, of which 10 were novel. There was a high incidence of previously reported recurrent mutations, occurring at 38.98% (23/59) of all cases. Of interest were three cases of mosaic RB1 mutations detected in the blood from patients with unilateral retinoblastoma. Additionally, two germline mutations previously reported to be associated with low-penetrance phenotypes: missense-c.1981C>T and splice variantc.607+1G>T, were observed in a bilateral and a unilateral proband, respectively. These findings have implications for genetic counselling and risk prediction for the affected families. This is the first published report on the spectrum of mutations in RB patients from Singapore and shows that further improved mutation screening strategies are required in order to provide a definitive molecular diagnosis for every case of RB. Our findings also underscore the importance of genetic testing in supporting individualized disease management plans for patients and asymptomatic family members carrying low-penetrance, germline mosaicism or heritable unilateral mutational phenotypes.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 87%

Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling

et al. 2017

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“…3,5,[12][13][14]33,34 Recently, a stepwise protocol was developed for the genetic analysis of Tunisian families. 17 Our strategy had notable differences, including the order of analysis and the method of selection of exons for various steps.…”

Section: Discussionmentioning

confidence: 99%

A stepwise strategy for rapid and cost-effective RB1 screening in Indian retinoblastoma patients

Thirumalairaj¹,

Abraham²,

Devarajan³

et al. 2015

J Hum Genet

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India has the highest number of retinoblastoma (RB) patients among the developing countries owing to its increasing population. Of the patients with RB, about 40% have the heritable form of the disease, making genetic analysis of the RB1 gene an integral part of disease management. However, given the large size of the RB1 gene with its widely dispersed exons and no reported hotspots, genetic testing can be cumbersome. To overcome this problem, we have developed a rapid screening strategy by prioritizing the order of exons to be analyzed, based on the frequency of nonsense mutations, deletions and duplications reported in the RB1-Leiden Open Variation Database and published literature on Indian patients. Using this strategy for genetic analysis, mutations were identified in 76% of patients in half the actual time and one third of the cost. This reduction in time and cost will allow for better risk prediction for siblings and offspring, thereby facilitating genetic counseling for families, especially in developing countries.

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“…The majority of germline mutations lead to 90% to 95% penetrance, and germline carriers usually develop bilateral or multifocal tumors (6). Nonsense and frameshift mutations in exons 2 to 25 almost always lead to highly penetrant bilateral RB, and they are the most frequent types of mutations found among familial cases (31)(32)(33). The high penetrance is likely due to posttranscriptional nonsensemediated decay, leading to degradation of truncated mRNA transcripts (32).…”

Section: Hereditary Rb: Introductionmentioning

confidence: 99%

“…These patients are at risk not only for RB but also in transmitting this predisposition to offspring. Testing by next-generation sequencing will likely increase the rate of detection of germline mosaicism (31,(38)(39)(40).…”

Section: Hereditary Rb: Introductionmentioning

confidence: 99%

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

Kamihara

Bourdeaut

Foulkes

et al. 2017

Clinical Cancer Research

174

127

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Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the RB1 gene. Children with hereditary RB are also at risk for developing a midline intracranial tumor, most commonly pineoblastoma. We recommend intensive ocular screening for patients with germline RB1 mutations for retinoblastoma as well as neuroimaging for pineoblastoma surveillance. There is an approximately 20% risk of developing second primary cancers among individuals with hereditary RB, higher among those who received radiotherapy for their primary RB tumors. However, there is not yet a clear consensus on what, if any, screening protocol would be most appropriate and effective. Neuroblastoma (NB), an embryonal tumor of the sympathetic nervous system, accounts for 15% of pediatric cancer deaths. Prior studies suggest that about 2% of patients with NB have an underlying genetic predisposition that may have contributed to the development of NB. Germline mutations in ALK and PHOX2B account for most familial NB cases. However, other cancer predisposition syndromes, such as Li-Fraumeni syndrome, RASopathies, and others, may be associated with an increased risk for NB. No established protocols for NB surveillance currently exist. Here, we describe consensus recommendations on hereditary RB and NB from the AACR Childhood Cancer Predisposition Workshop.

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RB1mutation spectrum in a comprehensive nationwide cohort of retinoblastoma patients

Abstract: The frequency of the type of mutations in the RB1 gene in our unbiased national cohort is the same as the mutation spectrum described worldwide. Furthermore, our RB1 mutation detection regimen achieves a high scanning sensitivity.

Cited by 73 publications

References 46 publications

Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling

Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling

A stepwise strategy for rapid and cost-effective RB1 screening in Indian retinoblastoma patients

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

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