Identification of Genes Targeted by CpG Island Methylator Phenotype in Neuroblastomas, and Their Possible Integrative Involvement in Poor Prognosis

Abe, Masanobu; Watanabe, Naoko; McDonell, Nathalie; Takato, Tsuyoshi; Ohira, Miki; Nakagawara, Akira; Ushijima, Toshikazu

doi:10.1159/000139124

Cited by 50 publications

(44 citation statements)

References 65 publications

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“…In prostate cancer, the decrease of NPY expression is associated with aggressive clinical behavior [45]. In other studies, NPY was shown to be frequently hypermethylated in neuroblastomas [46], hepatocellular carcinoma tissues [47] and their promoter hypermethylation was correlated with inactivation of gene expression. More recently, DeMorrow and colleagues have demonstrated that the treatment of cholangiocarcinoma cells with NPY as well as in vitro and in vivo decreases both proliferation and migration [48].…”

Section: Discussionmentioning

confidence: 99%

Aberrant methylation of NPY, PENK, and WIF1 as a promising marker for blood-based diagnosis of colorectal cancer

Roperch¹,

Incitti

Forbin³

et al. 2013

BMC Cancer

112

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BackgroundDNA methylation is a well-known epigenetic mechanism involved in epigenetic gene regulation. Several genes were reported hypermethylated in CRC, althought no gene marker was proven to be individually of sufficient sensitivity or specificity in routine clinical practice. Here, we identified novel epigenetic markers and assessed their combined use for diagnostic accuracy.MethodsWe used methylation arrays on samples from several effluents to characterize methylation profiles in CRC samples and controls, as established by colonoscopy and pathology findings, and selected two differentially methylated candidate epigenetic genes (NPY, PENK). To this gene panel we added WIF, on the basis of being reported in literature as silenced by promoter hypermethylation in several cancers, including CRC. We measured their methylation degrees by quantitative multiplex-methylation specific PCR (QM-MSP) on 15 paired carcinomas and adjacent non-cancerous colorectal tissues and we subsequently performed a clinical validation on two different series of 266 serums, subdivided in 32 CRC, 26 polyps, 47 other cancers and 161 with normal colonoscopy. We assessed the results by receiver operating characteristic curve (ROC), using cumulative methylation index (CMI) as variable threshold.ResultsWe obtained CRC detection on tissues with both sensitivity and specificity of 100%. On serum CRC samples, we obtained sensitivity/specificity values of, e.g., 87%/80%, 78%/90% and 59%/95%, and negative predictive value/positive predictive value figures of 97%/47%, 95%/61% and 92%/70%. On serum samples from other cancers we obtained sensitivity/specificity of, e.g, 89%/25%, 43%/80% and 28%/91%.ConclusionsWe showed the potential of NPY, PENK, and WIF1 as combined epigenetic markers for CRC diagnosis, both in tissue and serum and tested their use as serum biomarkers in other cancers. We optimized a QM-MSP for simultaneously quantifying their methylation levels. Our assay can be an effective blood test for patients where CRC risk is present but difficult to assess (e.g. mild symptoms with no CRC family history) and who would therefore not necessarily choose to go for further examination. This panel of markers, if validated, can also be a cost effective screening tool for the detection of asymptomatic cancer patients for colonoscopy.

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Section: Discussionmentioning

confidence: 99%

Aberrant methylation of NPY, PENK, and WIF1 as a promising marker for blood-based diagnosis of colorectal cancer

Roperch¹,

Incitti

Forbin³

et al. 2013

BMC Cancer

112

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“…18,19 The concordant hypermethylation of multiple genes in cancer is defined as CIMP and has been identified in many tumors including NB. [4][5][6][7][8][9][10] In this tumor, the methylation of the PCDHB cluster, the most informative gene of the NB CIMP, is a promising biomarker of outcome and its predictive power was confirmed in independent sets of patients. 7,9 It is thus possible that if CIMP will be validated in prospective studies, it might be transferred to the clinical practice.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 In neuroblastoma (NB), a solid tumor of infancy, specific methylation biomarkers predictive of prognosis, or potentially useful to better classify the patients into risk groups, were identified and contributed to the definition of the CIMP in this tumor. [7][8][9][10] The protocadherin B cluster (PCDHB) includes genes that concur to define the methylator phenotype in NB. Because of the strong correlation between PCDHB methylation and patients' survival, this cluster is considered the most informative member of CIMP in NB, and its methylation essentially recapitulates the entire predictive power of the multigenic CIMP.…”

mentioning

confidence: 99%

A pyrosequencing assay for the quantitative methylation analysis of the PCDHB gene cluster, the major factor in neuroblastoma methylator phenotype

Banelli

Brigati

Vinci

et al. 2012

Laboratory Investigation

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Epigenetic alterations are hallmarks of cancer and powerful biomarkers, whose clinical utilization is made difficult by the absence of standardization and of common methods of data interpretation. The coordinate methylation of many loci in cancer is defined as 'CpG island methylator phenotype' (CIMP) and identifies clinically distinct groups of patients. In neuroblastoma (NB), CIMP is defined by a methylation signature, which includes different loci, but its predictive power on outcome is entirely recapitulated by the PCDHB cluster only. We have developed a robust and cost-effective pyrosequencing-based assay that could facilitate the clinical application of CIMP in NB. This assay permits the unbiased simultaneous amplification and sequencing of 17 out of 19 genes of the PCDHB cluster for quantitative methylation analysis, taking into account all the sequence variations. As some of these variations were at CpG doublets, we bypassed the data interpretation conducted by the methylation analysis software to assign the corrected methylation value at these sites. The final result of the assay is the mean methylation level of 17 gene fragments in the protocadherin B cluster (PCDHB) cluster. We have utilized this assay to compare the methylation levels of the PCDHB cluster between high-risk and very low-risk NB patients, confirming the predictive value of CIMP. Our results demonstrate that the pyrosequencing-based assay herein described is a powerful instrument for the analysis of this gene cluster that may simplify the data comparison between different laboratories and, in perspective, could facilitate its clinical application. Furthermore, our results demonstrate that, in principle, pyrosequencing can be efficiently utilized for the methylation analysis of gene clusters with high internal homologies.

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“…S4). The presence of NSD1 CpG island hypermethylation in neuroblastomas was not associated with the methylation status of the described CpG island methylator phenotype (CIMP) targets in this tumor type (35)(36)(37), such as RASSF1A (Kendall's tau b test, P ϭ 0.948), BLU (P ϭ 0.681), PCDHG4C4 (P ϭ 0.292), or CRYBA2 (P ϭ 0.519) (Fig. S5).…”

Section: Nsd1 Has Tumor Suppressor-like Properties In Cancer Cellsmentioning

confidence: 97%

Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma

Berdasco

Ropero

Setién

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

187

139

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Sotos syndrome is an autosomal dominant condition characterized by overgrowth resulting in tall stature and macrocephaly, together with an increased risk of tumorigenesis. The disease is caused by loss-of-function mutations and deletions of the nuclear receptor SET domain containing protein-1 (NSD1) gene, which encodes a histone methyltransferase involved in chromatin regulation. However, despite its causal role in Sotos syndrome and the typical accelerated growth of these patients, little is known about the putative contribution of NSD1 to human sporadic malignancies. Here, we report that NSD1 function is abrogated in human neuroblastoma and glioma cells by transcriptional silencing associated with CpG island-promoter hypermethylation. We also demonstrate that the epigenetic inactivation of NSD1 in transformed cells leads to the specifically diminished methylation of the histone lysine residues H4-K20 and H3-K36. The described phenotype is also observed in Sotos syndrome patients with NSD1 genetic disruption. Expression microarray data from NSD1-depleted cells, followed by ChIP analysis, revealed that the oncogene MEIS1 is one of the main NSD1 targets in neuroblastoma. Furthermore, we show that the restoration of NSD1 expression induces tumor suppressorlike features, such as reduced colony formation density and inhibition of cellular growth. Screening a large collection of different tumor types revealed that NSD1 CpG island hypermethylation was a common event in neuroblastomas and gliomas. Most importantly, NSD1 hypermethylation was a predictor of poor outcome in high-risk neuroblastoma. These findings highlight the importance of NSD1 epigenetic inactivation in neuroblastoma and glioma that leads to a disrupted histone methylation landscape and might have a translational value as a prognostic marker.cancer ͉ DNA methylation ͉ epigenetics ͉ histone ͉ overgrowth

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Identification of Genes Targeted by CpG Island Methylator Phenotype in Neuroblastomas, and Their Possible Integrative Involvement in Poor Prognosis

Cited by 50 publications

References 65 publications

Aberrant methylation of NPY, PENK, and WIF1 as a promising marker for blood-based diagnosis of colorectal cancer

Aberrant methylation of NPY, PENK, and WIF1 as a promising marker for blood-based diagnosis of colorectal cancer

A pyrosequencing assay for the quantitative methylation analysis of the PCDHB gene cluster, the major factor in neuroblastoma methylator phenotype

Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma

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