DNA methylation analysis of benign and atypical meningiomas: correlation between RUNX3 methylation and WHO grade

Majchrzak‐Celińska, Aleksandra; Paluszczak, Jarosław; Szalata, Marlena; Barciszewska, Anna‐Maria; Nowak, S.; Baer‐Dubowska, Wanda

doi:10.1007/s00432-015-1930-5

Cited by 18 publications

(14 citation statements)

References 30 publications

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“…Although IRF4, CCND2, TP53I3 exhibited high methylation levels in CCA patients, no correlation of their methylation status with patients' survival and clinical parameters was found. In addition, hypermethylation of RUNX3 (45), RASSF1 (46) and ALDH1A3 (47) was found in multiple tumors such as meningiomas, gliomas and glioblastoma, but in our study, they exhibited very low methylation levels which were the same levels of normal epithelial cells.…”

Section: Discussioncontrasting

confidence: 58%

Aberrant methylation of HTATIP2 and UCHL1 as a predictive biomarker for cholangiocarcinoma

et al. 2017

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Cholangiocarcinoma (CCA) is the most common primary liver cancer in Northeastern Thailand where liver fluke infection is highly endemic. Although aberrant DNA methylation in CCA has been reported by several investigators, little is known regarding the associations between them. In the present study, the results obtained from our previously published methylation array were analyzed and 10 candidate genes involved in DNA repair [protein phosphatase 4 catalytic subunit (PPP4C)], apoptosis [runt related transcription factor 3 (RUNX3), interferon regulatory factor 4 (IRF4), ubiquitin C‑terminal hydrolase L1 (UCHL1) and tumor protein p53 inducible protein 3 (TP53I3)], cell proliferation [cyclin D2 (CCND2) and Ras association domain family member 1 (RASSF1)], drug metabolism [aldehyde dehydrogenase 1 family member A3 (ALDH1A3) and solute carrier family 29 member 1 (SLC29A1)] and angiogenesis [human immunodeficiency virus‑1 tat interactive protein 2 (HTATIP2)] were selected for quantification of their methylation levels in 54 CCA and 19 adjacent normal tissues using methylation‑sensitive high‑resolution melting. The associations between the methylation status of the individual genes and clinical parameters were statistically analyzed. High methylation levels were observed in UCHL1, IRF4, CCND2, HTATIP2 and TP53I3. The median methylation level of UCHL1 was 57.3% (range, 3.15 to 88.7%) and HTATIP2 was 13.6% (range, 7.5 to 36.7%). By contrast, low methylation of HTATIP2 and UCHL1 was identified in adjacent normal tissues. The methylation status of HTATIP2 and UCHL1 was associated with patients' overall survival. CCA patients with high methylation of HTATIP2 and low methylation of UCHL1 exhibited longer overall survival. In addition, multivariate Cox regression analysis demonstrated that UCHL1 methylation was an independent factor for CCA with hazard ratio of 1.81 (95% confidence interval, 1.01‑3.25) in high methylation group. The combination of HTATIP2 and UCHL1 methylation status strongly supported their potential predictive biomarker in which patients with CCA who had high methylation of HTATIP2 and low methylation of UCHL1 showed longer overall survival than those with low HTATIP2 methylation and high UCHL1 methylation. In conclusion, the present study revealed the value of aberrant DNA methylation of HTATIP2 and UCHL1, which may serve as a potential predictive biomarker for CCA.

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Section: Discussioncontrasting

confidence: 58%

Aberrant methylation of HTATIP2 and UCHL1 as a predictive biomarker for cholangiocarcinoma

et al. 2017

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“…In the past, several studies focused on investigating promoter methylation mainly using a targeted approach for a limited number of genes [4,6–8,11,30,14,15,34,38,47]. With time, molecular advances allowed interrogation at a larger number of CpG loci [35] culminating with the methylation assays from Illumina (27k and 450k) interrogating approximately 27.000 and 450.000 CpG loci [74,21].…”

Section: Discussionmentioning

confidence: 99%

Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma

Olar

Wani

Wilson³

et al. 2017

Acta Neuropathol

153

118

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Meningioma is the most common primary brain tumor and carries a substantial risk of local recurrence. Methylation profiles of meningioma and their clinical implications are not well understood. We hypothesized that aggressive meningiomas have unique DNA methylation patterns that could be used to better stratify patient management. Samples (n=140) were profiled using the Illumina HumanMethylation450 BeadChip. Unsupervised modeling on a training set (n=89) identified 2 molecular methylation subgroups of meningioma (MM) with significantly different recurrence free survival (RFS) times between the groups: a prognostically unfavorable subgroup (MM-UNFAV) and a prognostically favorable subgroup (MM-FAV). This finding was validated in the remaining 51 samples and led to a baseline meningioma methylation classifier (bMMC) defined by 283 CpG loci (283-bMMC). To further optimize a recurrence predictor, probes subsumed within the baseline classifier were subject to additional modeling using a similar training/validation approach, leading to a 64-CpG loci meningioma methylation predictor (64-MMP). After adjustment for relevant clinical variables [WHO grade, mitotic index, Simpson grade, sex, location, and copy number aberrations (CNA)] multivariable analyses for RFS showed that the baseline methylation classifier was not significant (p=0.0793). The methylation predictor however was significantly associated with tumor recurrence (p<0.0001). CNA were extracted from the 450k intensity profiles. Tumor samples in the MM-UNFAV subgroup showed an overall higher proportion of CNAs compared to the MM-FAV subgroup tumors and the CNAs were complex in nature. CNAs in the MM-UNFAV subgroup included recurrent losses of 1p, 6q, 14q and 18q, and gain of 1q, all of which were previously identified as indicators of poor outcome. In conclusion, our analyses demonstrate robust DNA methylation signatures in meningioma that correlate with CNAs and stratify patients by recurrence risk.

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“…Why PTEN is overexpressed in meningioma relative to meninges (dura, N and NN), and if it is related to a higher level of E-cadherin, are not currently known. However, the PTEN promoter has been found to be hypomethylated in meningioma grades I and II [ 69 ], suggesting the contribution of epigenetic regulation.…”

Section: Discussionmentioning

confidence: 99%

Differentially Expressed MicroRNAs in Meningiomas Grades I and II Suggest Shared Biomarkers with Malignant Tumors

El-Gewely

Andreassen

Walquist

et al. 2016

Cancers

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Meningiomas represent the most common primary tumors of the central nervous system, but few microRNA (miRNA) profiling studies have been reported so far. Deep sequencing of small RNA libraries generated from two human meningioma biopsies WHO grades I (benign) and II (atypical) were compared to excess dura controls. Nineteen differentially expressed miRNAs were validated by RT-qPCR using tumor RNA from 15 patients and 5 meninges controls. Tumor suppressor miR-218 and miR-34a were upregulated relative to normal controls, however, miR-143, miR-193b, miR-451 and oncogenic miR-21 were all downregulated. From 10 selected putative mRNA targets tested by RT-qPCR only four were differentially expressed relative to normal controls. PTEN and E-cadherin (CDH1) were upregulated, but RUNX1T1 was downregulated. Proliferation biomarker p63 was upregulated with nuclear localization, but not detected in most normal arachnoid tissues. Immunoreactivity of E-cadherin was detected in the outermost layer of normal arachnoids, but was expressed throughout the tumors. Nuclear Cyclin D1 expression was positive in all studied meningiomas, while its expression in arachnoid was limited to a few trabecular cells. Meningiomas of grades I and II appear to share biomarkers with malignant tumors, but with some additional tumor suppressor biomarkers expression. Validation in more patients is of importance.

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DNA methylation analysis of benign and atypical meningiomas: correlation between RUNX3 methylation and WHO grade

Cited by 18 publications

References 30 publications

Aberrant methylation of HTATIP2 and UCHL1 as a predictive biomarker for cholangiocarcinoma

Aberrant methylation of HTATIP2 and UCHL1 as a predictive biomarker for cholangiocarcinoma

Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma

Differentially Expressed MicroRNAs in Meningiomas Grades I and II Suggest Shared Biomarkers with Malignant Tumors

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