Evidence of predisposing epimutation in retinoblastoma

Gelli, Elisa; Pinto, Anna Maria; Somma, Serena; Imperatore, Valentina; Cannone, Marta Giulia; Hadjistilianou, Theodora; Francesco, Sonia De; Galimberti, Daniela; Currò, Aurora; Bruttini, Mirella; Mari, Francesca; Renieri, Alessandra; Ariani, Francesca

doi:10.1002/humu.23684

Cited by 16 publications

(10 citation statements)

References 19 publications

(20 reference statements)

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“…The authors concluded that both genetic mutation and epimutation contributed to the retinoblastoma in this family. A rare epimutation in the RB1 gene was also identified from another recent study (38). The authors showed that germline DNA methylation was associated with silencing of the RB1 gene expression.…”

Section: Understanding Cancer From the Perspective Of Epigenetic Regusupporting

confidence: 52%

Understanding Cancer Through the Lens of Epigenetic Inheritance, Allele-Specific Gene Expression, and High-Throughput Technology

Lee

2019

Front. Oncol.

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Epigenetic information is characterized by its stable transmission during mitotic cell divisions and plasticity during development and differentiation. This duality is in contrast to genetic information, which is stable and identical in all cells in an organism with exception of immunoglobulin gene rearrangements in lymphocytes and somatic mutations in cancer cells. Allele-specific analysis of gene expression and epigenetic modifications provides a unique approach to studying epigenetic regulation in normal and cancer cells. Extension of Knudson's two-hits theory to include epigenetic alteration as a means to inactivate tumor suppressor genes provides better understanding of how genetic mutations and epigenetic alterations jointly contribute to cancer development. High-throughput technology has greatly accelerated cancer discovery. Large initiatives such as TCGA have shown that epigenetic components are frequent targets of mutations in cancer and these discoveries provide new insights into understanding cancer etiology and generate new opportunities for cancer therapeutics.

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Section: Understanding Cancer From the Perspective Of Epigenetic Regusupporting

confidence: 52%

Understanding Cancer Through the Lens of Epigenetic Inheritance, Allele-Specific Gene Expression, and High-Throughput Technology

Lee

2019

Front. Oncol.

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“…Although it is well known that methylation of the RB1 promoter is a rather frequent inactivating event in retinoblastoma cancer cells, the role of constitutive epimutations has been poorly investigated and it has long been controversial [120][121][122]. However, a recent study demonstrated that RB1 promoter methylation can act as the first 'hit' in rare cases of retinoblastoma [123]. The presence of mosaic promoter methylation segregating with the disease was demonstrated by MS-MLPA in the blood of one out of 50 retinoblastoma patients who tested negative for germline predisposing variants.…”

Section: Retinoblastomamentioning

confidence: 99%

DNA Methylation in the Diagnosis of Monogenic Diseases

Cerrato

Sparago

Ariani

et al. 2020

Genes

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DNA methylation in the human genome is largely programmed and shaped by transcription factor binding and interaction between DNA methyltransferases and histone marks during gamete and embryo development. Normal methylation profiles can be modified at single or multiple loci, more frequently as consequences of genetic variants acting in cis or in trans, or in some cases stochastically or through interaction with environmental factors. For many developmental disorders, specific methylation patterns or signatures can be detected in blood DNA. The recent use of high-throughput assays investigating the whole genome has largely increased the number of diseases for which DNA methylation analysis provides information for their diagnosis. Here, we review the methylation abnormalities that have been associated with mono/oligogenic diseases, their relationship with genotype and phenotype and relevance for diagnosis, as well as the limitations in their use and interpretation of results.

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“…For example, Lynch syndrome typically is caused by point mutations or deletions or duplications in one of the mismatch repair genes; however, both constitutional and mosaic epimutations in the promoters of MLH1 and MSH2 also have been reported 5‐7 . Constitutional promoter methylation of the RB1 gene has been documented in a child with unilateral retinoblastoma 8 . Mosaic epimutations of SDHC have been observed in patients with gastrointestinal stromal tumors 9 .…”

Section: Introductionmentioning

confidence: 99%

11p15.5 epimutations in children with Wilms tumor and hepatoblastoma detected in peripheral blood

Fiala

Ortiz

Kennedy

et al. 2020

Cancer

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Background Constitutional or somatic mosaic epimutations are increasingly recognized as a mechanism of gene dysregulation resulting in cancer susceptibility. Beckwith‐Wiedemann syndrome is the cancer predisposition syndrome most commonly associated with epimutation and is extremely variable in its phenotypic presentation, which can include isolated tumors. Because to the authors' knowledge large‐scale germline DNA sequencing studies have not included methylation analysis, the percentage of pediatric cancer predisposition that is due to epimutations is unknown. Methods Germline methylation testing at the 11p15.5 locus was performed in blood for 24 consecutive patients presenting with hepatoblastoma (3 patients) or Wilms tumor (21 patients). Results Six individuals with Wilms tumor and 1 patient with hepatoblastoma were found to have low‐level gain of methylation at imprinting control 1, and a child with hepatoblastoma was found to have loss of methylation at imprinting control 2. The loss of methylation at imprinting control 2 was found to be maternally inherited, despite not being associated with any detectable genomic alteration. Conclusions Overall, 33% of patients (8 of 24 patients) with Wilms tumor or hepatoblastoma were found to have an epigenetic susceptibility that was detectable in the blood. It is interesting to note that low‐level gain of methylation at imprinting control 1 predominantly was detected in females with bilateral Wilms tumors. Further studies in larger cohorts are needed to determine the efficacy of testing all patients with Wilms tumor or hepatoblastoma for 11p15.5 epimutations in the blood as part of DNA analysis because this hallmark of predisposition will not be detected by sequencing‐based approaches and detecting a cancer predisposition may modify treatment.

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Evidence of predisposing epimutation in retinoblastoma

Cited by 16 publications

References 19 publications

Understanding Cancer Through the Lens of Epigenetic Inheritance, Allele-Specific Gene Expression, and High-Throughput Technology

Understanding Cancer Through the Lens of Epigenetic Inheritance, Allele-Specific Gene Expression, and High-Throughput Technology

DNA Methylation in the Diagnosis of Monogenic Diseases

11p15.5 epimutations in children with Wilms tumor and hepatoblastoma detected in peripheral blood

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