Epigenetic and Copy Number Variation Analysis in Retinoblastoma by MS-MLPA

Livide, Gabriella; Epistolato, Maria Carmela; Amenduni, Mariangela; Disciglio, Vittoria; Marozza, Annabella; Mencarelli, Maria Antonietta; Toti, Paolo; Lazzi, Stefano; Hadjistilianou, Theodora; Francesco, Sonia De; D’Ambrosio, Alfonso; Renieri, Alessandra; Ariani, Francesca

doi:10.1007/s12253-012-9498-8

Cited by 44 publications

(37 citation statements)

References 70 publications

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“…And in fact, gross deletion or duplication, promoter methylation of the RB1 gene and MYCN amplification without RB1 mutation have been identified in RB tumors [2, 4, 7, 10, 14, 16, 17]. The aim of the current study was to understand the incidence of retinoblastoma in Guatemala and the nature of the RB1 mutations in patients with this intraocular tumor.…”

Section: Introductionmentioning

confidence: 98%

Increased incidence and disparity of diagnosis of retinoblastoma patients in Guatemala

Dean

Bendfeldt

et al. 2014

Cancer Letters

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Analysis of 327 consecutive cases at a pediatric referral hospital of Guatemala reveals that retinoblastoma accounts for 9.4% of all cancers and the estimated incidence is 7.0 cases/million children, higher than the United States or Europe. The number of familial cases is low, and there is a striking disparity in indigenous children due to late diagnosis, advanced disease, rapid progression and elevated mortality. Nine germline mutations in 18 patients were found; two known and five new mutations. Hypermethylation of RB1 was identified in 13% of the tumors. An early diagnosis program could identify cases at an earlier age and improve outcome of retinoblastoma in this diverse population.

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Section: Introductionmentioning

confidence: 98%

Increased incidence and disparity of diagnosis of retinoblastoma patients in Guatemala

Dean

Bendfeldt

et al. 2014

Cancer Letters

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“…Being based on a single CpG site and analyzing only a small part of the promoter, MLPA cannot provide a complete profile of the methylation status of all CpG sites in a single gene. When using MLPA, a cutoff ratio calculated by dividing the relative peak area of each target probe by that of the undigested sample ranging from 15% to 30% is used 37, 38, 39. In this study, methylation was scored when the ratio was found to be more than 15%.…”

Section: Discussionmentioning

confidence: 99%

Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in oligodendroglial tumors

Kuo

Lee

et al. 2016

Cancer Medicine

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Aberrant methylation has been associated with transcriptional inactivation of tumor‐related genes in a wide spectrum of human neoplasms. The influence of DNA methylation in oligodendroglial tumors is not fully understood. Genomic DNA was isolated from 61 oligodendroglial tumors for analysis of methylation using methylation‐specific multiplex ligation‐dependent probe amplification assay (MS‐MLPA). We correlated methylation status with clinicopathological findings and outcome. The genes found to be most frequently methylated in oligodendroglial tumors were RASSF1A (80.3%), CASP8 (70.5%), and CDKN2A (52.5%). Kaplan–Meier survival curve analysis demonstrated longer duration of progression‐free survival in patients with 19q loss, aged less than 38 years, and with a proliferative index of less than 5%. Methylation of the ESR1 promoter is significantly associated with shorter duration of overall survival and progression‐free survival, and that methylation of IGSF4 and RASSF1A is significantly associated with shorter duration of progression‐free survival. However, none of the methylation status of ESR1, IGSF4, and RASSF1A was of prognostic value for survival in a multivariate Cox model. A number of novel and interesting epigenetic alterations were identified in this study. The findings highlight the importance of methylation profiles in oligodendroglial tumors and their possible involvement in tumorigenesis.

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“…The retinoblastoma protein ( pRB ) promoter region is rich in CpG sites within its CpG islands and the promoter sequence is frequently methylated and silenced in certain human tumours [251,252,253]. In order to gauge the contribution of CTCF to the silencing events, an siRNA experiment against the CTCF gene was conducted in HeLa cells [254,255].…”

Section: Ctcf and Control Of Epigenetic Modifications In Tsgsmentioning

confidence: 99%

A Tox21 Approach to Altered Epigenetic Landscapes: Assessing Epigenetic Toxicity Pathways Leading to Altered Gene Expression and Oncogenic Transformation In Vitro

Parfett

Desaulniers

2017

IJMS

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An emerging vision for toxicity testing in the 21st century foresees in vitro assays assuming the leading role in testing for chemical hazards, including testing for carcinogenicity. Toxicity will be determined by monitoring key steps in functionally validated molecular pathways, using tests designed to reveal chemically-induced perturbations that lead to adverse phenotypic endpoints in cultured human cells. Risk assessments would subsequently be derived from the causal in vitro endpoints and concentration vs. effect data extrapolated to human in vivo concentrations. Much direct experimental evidence now shows that disruption of epigenetic processes by chemicals is a carcinogenic mode of action that leads to altered gene functions playing causal roles in cancer initiation and progression. In assessing chemical safety, it would therefore be advantageous to consider an emerging class of carcinogens, the epigenotoxicants, with the ability to change chromatin and/or DNA marks by direct or indirect effects on the activities of enzymes (writers, erasers/editors, remodelers and readers) that convey the epigenetic information. Evidence is reviewed supporting a strategy for in vitro hazard identification of carcinogens that induce toxicity through disturbance of functional epigenetic pathways in human somatic cells, leading to inactivated tumour suppressor genes and carcinogenesis. In the context of human cell transformation models, these in vitro pathway measurements ensure high biological relevance to the apical endpoint of cancer. Four causal mechanisms participating in pathways to persistent epigenetic gene silencing were considered: covalent histone modification, nucleosome remodeling, non-coding RNA interaction and DNA methylation. Within these four interacting mechanisms, 25 epigenetic toxicity pathway components (SET1, MLL1, KDM5, G9A, SUV39H1, SETDB1, EZH2, JMJD3, CBX7, CBX8, BMI, SUZ12, HP1, MPP8, DNMT1, DNMT3A, DNMT3B, TET1, MeCP2, SETDB2, BAZ2A, UHRF1, CTCF, HOTAIR and ANRIL) were found to have experimental evidence showing that functional perturbations played “driver” roles in human cellular transformation. Measurement of epigenotoxicants presents challenges for short-term carcinogenicity testing, especially in the high-throughput modes emphasized in the Tox21 chemicals testing approach. There is need to develop and validate in vitro tests to detect both, locus-specific, and genome-wide, epigenetic alterations with causal links to oncogenic cellular phenotypes. Some recent examples of cell-based high throughput chemical screening assays are presented that have been applied or have shown potential for application to epigenetic endpoints.

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Epigenetic and Copy Number Variation Analysis in Retinoblastoma by MS-MLPA

Cited by 44 publications

References 70 publications

Increased incidence and disparity of diagnosis of retinoblastoma patients in Guatemala

Increased incidence and disparity of diagnosis of retinoblastoma patients in Guatemala

Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in oligodendroglial tumors

A Tox21 Approach to Altered Epigenetic Landscapes: Assessing Epigenetic Toxicity Pathways Leading to Altered Gene Expression and Oncogenic Transformation In Vitro

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