Retinoblastoma: Etiology, Modeling, and Treatment

Kaewkhaw, Rossukon; Rojanaporn, Duangnate

doi:10.3390/cancers12082304

Cited by 73 publications

(68 citation statements)

References 171 publications

(381 reference statements)

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“…Human retinoblastoma is primarily comprised of cone-like cells and has been recognized as being associated with high or low expression of cone genes. 7 , 17 , 20 , 29 , 30 MYCN -driven retinoblastoma is in the group characterized by low expression of cone-associated genes, 7 and expression of cone-associated genes was further downregulated following MYCNOS1 depletion. This change in expression of cone genes is not a result of differential death; rather, it could result from a switch in cell fate in tumors deficient for MYCNOS1 ( Figs.…”

Section: Discussionmentioning

confidence: 99%

“… 33 Loss of a cone gene signature is suggestive of tumor progression, involving enriched expression of progenitor or neuronal genes. 29 However, it is unlikely that cells deficient for MYCNOS1 represent advanced tumor cells, because they exhibit reduced aggressive behaviors. We hypothesize that MYCNOS1 maintains the features of retinoblastoma/cone signature or “stemness” previously reported for MYCNOS2 34 and that loss of MYCNOS1 expression induces neuronal differentiation in MYCN -amplified retinoblastoma without RB1 mutation.…”

Section: Discussionmentioning

confidence: 99%

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Silencing of the Long Noncoding RNAMYCNOS1Suppresses Activity ofMYCN-Amplified Retinoblastoma WithoutRB1Mutation

Saengwimol

Chittavanich

Laosillapacharoen

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. MYCNOS (MYCN opposite strand) is co-amplified with MYCN in pediatric cancers, including retinoblastoma. MYCNOS encodes several RNA variants whose functions have not been elucidated in retinoblastoma. Thus, we attempted to identify MYCNOS variants in retinoblastoma and aimed to decipher the role of MYCNOS variant 1 (MYCNOS1) on the activity of MYCN-amplified retinoblastoma. METHODS. The profiles of MYCNOS variants and MYCN status were determined in 17 retinoblastoma tissues, cell lines, retinas, and retinal organoids. A functional study of MYCNOS1 expression was conducted in patient-derived tumor cells and in retinoblastoma cell lines via short hairpin RNA-mediated gene silencing. We carried out MYCN expression, cell viability, cell cycle, apoptosis, soft agar colony formation, and transwell assays to examine the role of MYCNOS1 in MYCN and cell behaviors. We analyzed a transcriptome of MYCN-amplified retinoblastoma cells deficient for MYCNOS1 and, finally, tested the responses of these cells to chemotherapeutic agents. RESULTS. Expression of MYCNOS1 was associated with the expression and copy number of MYCN. Knockdown of MYCNOS1 caused instability of the MYCN protein, leading to cell cycle arrest and impaired proliferation and chemotaxis-directed migration in MYCNamplified retinoblastoma cells in which RB1 was intact. MYCNOS1 expression was associated with gene signatures of photoreceptor cells and epithelial-mesenchymal transition. MYCNOS1 silencing enhanced the response of retinoblastoma cells to topotecan but not carboplatin. CONCLUSIONS. MYCNOS1 supports progression of retinoblastoma. Inhibition of MYCNOS1 expression may be necessary to suppress MYCN activity when treating MYCN-amplified cancers without RB1 mutation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Silencing of the Long Noncoding RNAMYCNOS1Suppresses Activity ofMYCN-Amplified Retinoblastoma WithoutRB1Mutation

Saengwimol

Chittavanich

Laosillapacharoen

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…Primary treatments for intraocular disease include enucleation, intravenous CT (melphalan with or without topotecan and/or carboplatin) with focal therapy (laser therapy, cryotherapy), intra-arterial CT with focal therapy, and focal therapy alone when tumors are small at diagnosis [ 423 ]. The choice of treatment is based on the likelihood of tumor control, eye salvage, ultimate vision, and the status of the other eye weighed against acute and chronic consequences of treatment.…”

Section: Childhood Cancer and Second Primary Malignanciesmentioning

confidence: 99%

“…RB patients with germline RB1 mutation who received EBRT have a high risk of 50% to develop SPMs with advanced age including leiomyosarcoma, OS, melanoma, lung, and bladder cancer [ 426 ]. Currently, several molecular targets such as SKP2 (e.g., via the NEDD8-inhibitor pevonedistat), MDM2, histone deacetylases, or the TRK SYK are being discussed for the treatment of CT-resistant RB to improve cure rates while reducing treatment-related side effects [ 423 ].…”

Section: Childhood Cancer and Second Primary Malignanciesmentioning

confidence: 99%

Childhood Cancer: Occurrence, Treatment and Risk of Second Primary Malignancies

Zahnreich

Schmidberger

2021

Cancers

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Cancer represents the leading cause of disease-related death and treatment-associated morbidity in children with an increasing trend in recent decades worldwide. Nevertheless, the 5-year survival of childhood cancer patients has been raised impressively to more than 80% during the past decades, primarily attributed to improved diagnostic technologies and multiagent cytotoxic regimens. This strong benefit of more efficient tumor control and prolonged survival is compromised by an increased risk of adverse and fatal late sequelae. Long-term survivors of pediatric tumors are at the utmost risk for non-carcinogenic late effects such as cardiomyopathies, neurotoxicity, or pneumopathies, as well as the development of secondary primary malignancies as the most detrimental consequence of genotoxic chemo- and radiotherapy. Promising approaches to reducing the risk of adverse late effects in childhood cancer survivors include high precision irradiation techniques like proton radiotherapy or non-genotoxic targeted therapies and immune-based treatments. However, to date, these therapies are rarely used to treat pediatric cancer patients and survival rates, as well as incidences of late effects, have changed little over the past two decades in this population. Here we provide an overview of the epidemiology and etiology of childhood cancers, current developments for their treatment, and therapy-related adverse late health consequences with a special focus on second primary malignancies.

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“…Since the 1980s, the RB1 gene on the long arm of chromosome 13 (13q14) has been recognized as the RB tumor suppressor gene for the first time, and its pathogenic variant is involved in the occurrence of RB [5,6,[8][9][10]. Compelling studies [1,5,6,[11][12][13][14][15] indicated that the RB1 gene is an allele encoding retinoblastoma protein (pRB), and the lack of monitoring or inactivation of RB1 will lead to a decline in cell proliferation regulation function thus resulting in abnormal cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Correlation between Family RB1 Gene Pathogenic Variant with Clinical Features and Prognosis of Retinoblastoma under 5 Years Old

et al. 2021

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Retinoblastoma (RB) is the most common primary intraocular malignant tumor in infants and the prototype of human hereditary tumors. Its occurrence and development are closely related to the pathogenic variant of tumor suppressor RB1 gene. We aim to analyze the characteristics of RB1 gene pathogenic variant and clinical phenotype in retinoblastoma patients and their relatives. Children with RB were recruited from August 2007 to November 2017. QT-PCR, probing, and gene sequencing were used to analyze the sequence of RB1 gene in RB children, their parents, or grandparents with a clear history of illness. The SPSS20.0 software was used to analyze the correlation between polymorphisms of RB1 gene and the incidence and prognosis of the enrolled children and relatives. 40 RB children (20 males and 20 females) were recruited, unilateral RB accounted for 52.5% (21/40), bilateral RB accounted for 42.5% (17/40), and trilateral RB accounted for 5.0% (2/40). 6 patients had a clear family history (15.0%, 6/40). It had been verified that 19 probands (47.5%) have RB1 gene pathogenic variants (11 frameshift and 8 missense pathogenic variants), of which germline inheritance accounted for 47.4% (9/19) and nongermline heredity accounted for 52.6% (10/19). Pathogenic variants of 10 nucleic acid sites without reported were found, among which c.2455C>G (p.L819V) was confirmed to have heterozygous pathogenic variants in both a bilateral RB patient and his mother with unilateral RB. Family genetic high-risk factors, bilateral/trilateral RB, >12-month-onset RB have a higher proportion of RB1 gene pathogenic variant than children with no family history, unilateral RB, and ≤12-month ( P = 0.021 , 0.001,0.034). The proportion of pedigree inheritance of infantile retinoblastoma with bilateral disease is high. There was a certain proportion of RB1 gene pathogenic variant in 3-5-year-old children with bilateral RB, even if they had no family genetic history. Therefore, the detection of RB1 gene pathogenic variant should not only focus on infants but also on the phenotype of RB1 gene pathogenic variant in children over 3 years old with bilateral eye disease.

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Retinoblastoma: Etiology, Modeling, and Treatment

Cited by 73 publications

References 171 publications

Silencing of the Long Noncoding RNAMYCNOS1Suppresses Activity ofMYCN-Amplified Retinoblastoma WithoutRB1Mutation

Silencing of the Long Noncoding RNAMYCNOS1Suppresses Activity ofMYCN-Amplified Retinoblastoma WithoutRB1Mutation

Childhood Cancer: Occurrence, Treatment and Risk of Second Primary Malignancies

Correlation between Family RB1 Gene Pathogenic Variant with Clinical Features and Prognosis of Retinoblastoma under 5 Years Old

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