The impact of RB1 genotype on incidence of second tumours in heritable retinoblastoma

Ketteler, Petra; Hülsenbeck, Isabel; Frank, Mirjam; Schmidt, Börge; Jöckel, Karl‐Heinz; Lohmann, Dietmar

doi:10.1016/j.ejca.2020.04.005

Cited by 17 publications

(11 citation statements)

References 32 publications

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“…Previous studies have suggested that age of onset and incidence of SPM in individuals with heritable retinoblastoma are influenced by the type of pathogenic RB1 allele, and risk is highest in children with variants that are regularly associated with complete penetrance for retinoblastoma [25,26]. Analysis of risk to SPM is complicated because external factors, especially treatment with external beam radiotherapy (EBRT), have a strong impact on the incidence.…”

Section: Discussionmentioning

confidence: 99%

“…Some patients also show retinoma, which are essentially benign retinal lesions, or develop embryonic midline tumors such as pineoblastoma [21][22][23]. Patients with heritable retinoblastoma have a higher risk of extraocular malignancies (second primary malignancies, SPM) later in life compared to children without constitutional RB1 variant [24][25][26]. The spectrum of phenotypic expression of heritable retinoblastoma includes incomplete penetrance, which is defined as the absence of retinoblastoma or retinoma in an adult who is heterozygous for a pathogenic RB1 allele.…”

Section: Introductionmentioning

confidence: 99%

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Introduction of a Variant Classification System for Analysis of Genotype-Phenotype Relationships in Heritable Retinoblastoma

Hülsenbeck

Frank

Biewald

et al. 2021

Cancers

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Constitutional haploinsufficiency of the RB1 gene causes heritable retinoblastoma, a tumor predisposition syndrome. Patients with heritable retinoblastoma develop multiple retinoblastomas early in childhood and other extraocular tumors later in life. Constitutional pathogenic variants in RB1 are heterogeneous, and a few genotype-phenotype correlations have been described. To identify further genotype-phenotype relationships, we developed the retinoblastoma variant effect classification (REC), which considers each variant’s predicted effects on the common causal mediator, RB1 protein pRB. For validation, the RB1 variants of 287 patients were grouped according to REC. Multiple aspects of phenotypic expression were analyzed, known genotype-phenotype associations were revised, and new relationships were explored. Phenotypic expression of patients with REC-I, -II, and -III was distinct. Remarkably, the phenotype of patients with variants causing residual amounts of truncated pRB (REC-I) was more severe than patients with complete loss of RB1 (REC-II). The age of diagnosis of REC-I variants appeared to be distinct depending on truncation’s localization relative to pRB structure domains. REC classes identify genotype-phenotype relationships and, therefore, this classification framework may serve as a tool to develop tailored tumor screening programs depending on the type of RB1 variant.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Introduction of a Variant Classification System for Analysis of Genotype-Phenotype Relationships in Heritable Retinoblastoma

Hülsenbeck

Frank

Biewald

et al. 2021

Cancers

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“…External radiotherapy is the main risk factor for soft-tissue sarcoma and osteosarcoma in the radiation field. The incidence of SMNs was four times higher in survivors heterozygous for an oncogenic Rb1 variant than with Rb1 mosaicism [52].…”

Section: Genetic Syndromesmentioning

confidence: 89%

Possible Mechanisms of Subsequent Neoplasia Development in Childhood Cancer Survivors: A Review

Kruseová

Vícha

Feriančiková

et al. 2021

Cancers

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Advances in medicine have improved outcomes in children diagnosed with cancer, with overall 5-year survival rates for these children now exceeding 80%. Two-thirds of childhood cancer survivors have at least one late effect of cancer therapy, with one-third having serious or even life-threatening effects. One of the most serious late effects is a development of subsequent malignant neoplasms (histologically different cancers, which appear after the treatment for primary cancer), which occur in about 3–10% of survivors and are associated with high mortality. In cancers with a very good prognosis, subsequent malignant neoplasms significantly affect long-term survival. Therefore, there is an effort to reduce particularly hazardous treatments. This review discusses the importance of individual factors (gender, genetic factors, cytostatic drugs, radiotherapy) in the development of subsequent malignant neoplasms and the possibilities of their prediction and prevention in the future.

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“…In the non-hereditary form, the risk of disease transmission is only 5%, while in the hereditary form, the risk increases to 50% (8). The only cause of RB is a mutation in the RB1 gene following point mutations (nonsense (frameshift, splicing missense) or mutation in the promoter region of the gene), and to date, no other factors have been reported to affect the onset of the disease (9,10). There are four possible sources for RB disease: retinal cells, retinal stem cells (progenitor), neuronal, and glial cells, and finally, mitotic cells are involved in the produc-tion of retinal cells in humans (11).…”

Section: Introductionmentioning

confidence: 99%

The Concordance of Paternal and Maternal Retinoblastoma-1 Gene Mutation Pattern with Clinical Manifestation and Disease Staging in Patients Suffering from Retinoblastoma

Moghadam¹,

Faranoush²,

Moghadam³

et al. 2022

Zahedan J Res Med Sci

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Background: Retinoblastoma (RB) is a common neoplastic disease in children, leading to high mortality if not diagnosed and treated timely. Mutations in both versions of the Retinoblastoma1 (RB1) gene are responsible for this disease. A wide range of mutations has been reported throughout the RB1 gene. Objectives: The present study aimed to assess the concordance of paternal and maternal RB-1 gene mutation with clinical manifestation and disease staging in patients suffering from RB. Methods: This cross-sectional study was performed on 23 patients with unilateral or bilateral RB. Paternal and maternal peripheral blood samples were extracted for genome analysis. Information related to clinical manifestations and disease staging was collected from the patients’ hospital records. Multiplex-ligation dependent probe amplification (MLPA) method or Sanger sequencing method was employed to assess the gene mutation and its genomic pattern. Results: No significant association was revealed between the presence of both maternal and paternal RB1 gene mutations and the disease staging, while the study could show a significant relationship between the presence and heterozygous pattern of RB1 gene mutation and the presence of disease-related clinical manifestations that bilateral involvement was strongly associated with the presence of a heterozygous pattern of gene mutation compared to unilateral involvement (P = 0.001). Conclusions: This study showed a significant correlation between the presence of RB1 gene mutation and bilateral involvement in RB, but the association between the disease staging and gene mutation remains insignificant.

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The impact of RB1 genotype on incidence of second tumours in heritable retinoblastoma

Cited by 17 publications

References 32 publications

Introduction of a Variant Classification System for Analysis of Genotype-Phenotype Relationships in Heritable Retinoblastoma

Introduction of a Variant Classification System for Analysis of Genotype-Phenotype Relationships in Heritable Retinoblastoma

Possible Mechanisms of Subsequent Neoplasia Development in Childhood Cancer Survivors: A Review

The Concordance of Paternal and Maternal Retinoblastoma-1 Gene Mutation Pattern with Clinical Manifestation and Disease Staging in Patients Suffering from Retinoblastoma

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