The methylation of a panel of genes differentiates low-grade from high-grade gliomas

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

doi:10.1007/s13277-014-3025-3

Cited by 22 publications

(23 citation statements)

References 38 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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“…Our previous study has shown that a panel of 12 genes including ERCC1 , hMLH1 , ATM , CDKN2B ( p15INK4B ), p14ARF , CDKN2A ( p16INK4A ), RASSF1A , RUNX3 , GATA6 , NDRG2 , PTEN , and RARβ might be useful in evaluation of glioma aggressiveness. In this regard, methylation index (MI) of these genes in individual patient, as well as RUNX3 methylation correlated with glioma WHO grade and higher MI, or aberrant methylation of RUNX3 indicated more aggressive tumors (Majchrzak-Celińska et al 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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

Majchrzak‐Celińska

Paluszczak

Szalata

et al. 2015

J Cancer Res Clin Oncol

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PurposeAlthough meningiomas are common central nervous system tumors, the biomarkers allowing early diagnosis and progression are still needed. The aim of this study was to evaluate the methylation status of 12 cancer-related genes, namely ERCC1, hMLH1, ATM, CDKN2B (p15INK4B), p14ARF, CDKN2A (p16INK4A), RASSF1A, RUNX3, GATA6, NDRG2, PTEN, and RARβ, in 44 meningioma samples of WHO grade I and II.MethodsAll genes were analyzed using methylation-specific polymerase chain reaction, while pyrosequencing (PSQ) was used to study NDRG2 promoter methylation.ResultsThe most frequently methylated genes in both types of meningiomas were p14ARF, RASSF1A, and p15INK4B. RUNX3, GATA6, and p16INK4A were methylated to a lesser extent, whereas ATM and RARβ were found to be methylated in a marginal number of patients. The ERCC1, hMLH1, NDRG2, and PTEN genes were unmethylated in all cases. Although tumors of the same grade according to WHO criteria had different genes methylated, the number of methylated genes for each individual patient was low. RUNX3 methylation significantly correlated with meningioma WHO grade, therefore, can be considered as a potential indicator of tumor aggressiveness. The sequence of NDRG2 chosen for PSQ analysis was found methylated in the majority of meningiomas; however, the methylation level was only slightly elevated as compared to non-cancerous brain.ConclusionsOverall, the results of this study confirm that DNA methylation plays an important role in the pathogenesis of meningiomas. Further investigations, particularly concerning RUNX3 methylation, are necessary in order to assess the clinical usefulness of the methylation analysis of the studied genes.

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“…Epigenetic changes, including aberrant DNA methylation, are important in the pathogenesis of glial tumours (4,14). Thus, the search for novel methylation biomarkers or the validation of already identified methylation biomarkers, which may facilitate glioma diagnosis, prognosis or treatment decisions, remains a current issue (14).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the search for novel methylation biomarkers or the validation of already identified methylation biomarkers, which may facilitate glioma diagnosis, prognosis or treatment decisions, remains a current issue (14). In the present study, the methylation status of the TES gene, which has the potential to be used in routine clinical setting as a biomarker for astrocytomas of different malignancy grade, was analysed.…”

Section: Discussionmentioning

confidence: 99%

Testin (TES) as a candidate tumour suppressor and prognostic marker in human astrocytoma

et al. 2016

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Astrocytomas are one of the most common brain tumours; however, the current methods used to characterize these tumours are inadequate. The establishment of molecular markers may identify variables required to improve tumour characterization and subtyping, and may aid to specify targets for improved treatment with essential prognostic value for patient survival. One such candidate is testin (TES), which was reported to have prognostic value for glioblastoma patients. However, the role of TES protein in gliomagenesis is currently unknown. In the present study, the methylation status of the TES promoter was investigated in post-operative astrocytoma tumours of different malignancy grade, and its association with the survival of astrocytoma patients was evaluated. In addition, the expression of TES protein was investigated in the same set of astrocytoma tumours tissue, and the association of protein expression with glioma patients survival was evaluated. The methylation status of TES was assessed by methylation-specific polymerase chain reaction in 138 different grade astrocytoma samples. Western blot analysis was used to characterize the expression pattern of TES in 86 different grade astrocytoma specimens: 13 of pathological grade I, 31 of pathological grade II, 17 of pathological grade III and 25 of pathological grade IV (glioblastoma). Statistical analyses were conducted to investigate the association between tumour molecular pattern, patient clinical variables and overall survival. The methylation analysis of the TES promoter exhibited a distinct profile between astrocytomas of different malignancy grade (P<0.001). Furthermore, gene promoter methylation was significantly associated with patients' age, survival and pathological grade (P<0.001). The protein expression level of TES was significantly lower in glioblastoma (grade IV astrocytoma) than in lower grade (II–III) astrocytoma tissue (P=0.028 and P=0.04, respectively). Additionally, short overall survival of patients was markedly associated with low TES protein expression (P=0.007). However, no association between TES methylation and TES protein expression was noticed. The present study demonstrated that decreased expression of TES may be important in tumour progression and prognosis in human astrocytomas. TES may be a useful marker for predicting the clinical outcome of astrocytoma patients.

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The methylation of a panel of genes differentiates low-grade from high-grade gliomas

Cited by 22 publications

References 38 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

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

Testin (TES) as a candidate tumour suppressor and prognostic marker in human astrocytoma

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