Enhanced Sensitivity for Detection of Low-Level Germline Mosaic<i>RB1</i>Mutations in Sporadic Retinoblastoma Cases Using Deep Semiconductor Sequencing

Zhao, Chen; Moran, Kimberly; Richards‐Yutz, Jennifer; Toorens, Erik; Gerhart, Daniel; Ganguly, Tapan; Shields, Carol L.; Ganguly, Arupa

doi:10.1002/humu.22488

Cited by 78 publications

(73 citation statements)

References 12 publications

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“…However, as stated by Knudson in 1971, 10-15% of non-familial, unilateral cases are heritable [1]. This high percentage was indeed confirmed in recent data in which a mutation was found in 18% of sporadic unilateral cases [3].…”

supporting

confidence: 59%

“…Recently, the incidence of germline mutations in sporadic unilateral patients has been reported as high as 18%, with several cases of low-level mosaic mutations identified using deep sequencing techniques [3]. Since the introduction of routine testing in patients with sporadic unilateral unifocal disease in Denmark, one of 14 such patients (7%) has been identified with a germline mutation.…”

Section: Discussionmentioning

confidence: 99%

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Danish retinoblastoma patients 1943–2013 – genetic testing and clinical implications

et al. 2015

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Background: In heritable retinoblastoma there is a 50% risk of transmitting the RB1 mutation, and offspring carriers have more than 90% risk of developing retinoblastoma. Today, all newly diagnosed retinoblastoma patients in Denmark are screened for mutations in RB1, as opposed to only a minority of patients diagnosed before DNA testing was offered. Knowledge of heredity increases the chance of early diagnosis in offspring, leading to improved prognosis. We present data from the Danish retinoblastoma patients that emphasize the need for genetic counseling and RB1 screening in all untested retinoblastoma survivors. Material and methods: Data are extracted from The Danish Ocular Oncology Group Database, a national population database containing data on all Danish retinoblastoma patients since 1943. Results: In total 323 retinoblastoma patients have been diagnosed between 1943 and 2013. Since 1963, the rate has been stable around 1 per 14 000 live births with 95% of the patients surviving their retinoblastoma. Stratifying data on the time of diagnosis and status of genetic testing, the number of screened patients gradually increased from 5% in the beginning of the period to 96% in the last five-year period. A cohort of 181 retinoblastoma survivors with sporadic disease (15% heritable) did not receive genetic testing. Since the introduction of routine testing, one of 14 sporadic unilateral patients tested (7%) has been identified with a germline mutation. Before routine testing, five additional sporadic unilateral patients have been identified as heritable. Conclusion: Only a minority of Danish retinoblastoma patients diagnosed before routine genetic testing was offered have been RB1 screened. To counsel the remaining untested patients and their families sufficiently regarding the risk to offspring and elevated risk of second primary cancers, we recommend information and access to genetic counseling and RB1 screening. This has ethical, psychological and possible economic consequences, and should be handled with caution.

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supporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Danish retinoblastoma patients 1943–2013 – genetic testing and clinical implications

et al. 2015

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“…Individuals with these cytogenetic deletions may have dysmorphic facial features (most commonly anteverted ears, broad forehead, long philtrum) as well as varying levels of neurologic impairment, but the extent and severity of the abnormalities are likely due to the additional gene(s) encompassed by the germline deletion (35,37). In addition, germline mosaicism for RB1 mutations has been estimated to occur in approximately 6% of unilateral cases (38). These patients are at risk not only for RB but also in transmitting this predisposition to offspring.…”

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

188

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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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“…4 To shed light on this issue, we specifically designed a study to address the recurrence risk in unaffected parents tested negative for the mutation identified in their affected sibling. We took advantage of deep sequencing which increases the sensitivity of mutation detection, increases the number of mosaics detected 11 and as a result, may refine recurrence risk rates. We added a complementary analysis of recurrence based on a new predictive model.…”

Section: Discussionmentioning

confidence: 99%

Mosaicism and prenatal diagnosis options: insights from retinoblastoma

et al. 2016

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In sporadic cases, a post-zygotic mutational event signifies a somatic mosaicism in the affected child only, which implies that these mutations affect only a portion of the body. Therefore siblings do not need follow-up. On the other hand, a pre-zygotic mutation transmitted by an unaffected mosaic parent implies recurrent risks in offspring. To better estimate the contribution of pre-and post-zygotic events, we analysed 124 consecutive bilateral retinoblastoma probands, carrying a heterozygous RB1 pathogenic variant and their unaffected, non-carrier parents. In order to evaluate somatic mosaicism in blood, the deleterious RB1 pathogenic variant identified in the proband, was searched for in the unaffected parents, using targeted deep sequencing. Observed recurrences, which represent an estimation of germline and somatic mosaicisms, were recorded and computed in the sibships. Deep sequencing revealed one mosaic-unaffected parent out of 124 tested couples, which provides an estimation of the maximal risk of recurrence, due to parental mosaicism, at 0.4%. Follow-up in the sibships showed one recurrence, providing a maximal recurrence risk, due to parental mosaicism, at 0.8%. Two different statistical strategies led to close estimates (0.4 and 0.8% risks) which appeared 266-533-fold higher, as compared with the general population. These recurrence estimates could be considered when counselling couples with retinoblastoma or diseases with a high de novo mutation rate.

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Enhanced Sensitivity for Detection of Low-Level Germline MosaicRB1Mutations in Sporadic Retinoblastoma Cases Using Deep Semiconductor Sequencing

Cited by 78 publications

References 12 publications

Danish retinoblastoma patients 1943–2013 – genetic testing and clinical implications

Danish retinoblastoma patients 1943–2013 – genetic testing and clinical implications

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

Mosaicism and prenatal diagnosis options: insights from retinoblastoma

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