Marked and independent prognostic significance of the CpG island methylator phenotype in neuroblastomas

Abe, Masanobu; Westermann, Frank; Nakagawara, Akira; Takato, Tsuyoshi; Schwab, Manfred; Ushijima, Toshikazu

doi:10.1016/j.canlet.2006.05.001

Cited by 47 publications

(66 citation statements)

References 16 publications

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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.

186

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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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.

186

139

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“…[20][21][22], hepatocellular (23)(24)(25)(26), lung (27,28), ovarian (29), pancreatic (30), prostate (31), and renal cell (32) cancers, as well as in leukemia (33)(34)(35)(36), melanoma (37), duodenal adenocarninomas (38), adrenocortical carcinomas (39), and neuroblastomas (40,41). The primary purpose of these studies was to determine if CIMP is also present in these cancers, and if it can be used to distinguish between known phenotypes of the respective cancer type.…”

Section: Introductionmentioning

confidence: 99%

The CpG Island Methylator Phenotype: What's in a Name?

et al. 2013

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Although the CpG island methylator phenotype (CIMP) was first identified and has been most extensively studied in colorectal cancer, the term "CIMP" has been repeatedly used over the past decade to describe CpG island promoter methylation in other tumor types, including bladder, breast, endometrial, gastric, glioblastoma (gliomas), hepatocellular, lung, ovarian, pancreatic, renal cell, and prostate cancers, as well as for leukemia, melanoma, duodenal adenocarninomas, adrenocortical carcinomas, and neuroblastomas. CIMP has been reported to be useful for predicting prognosis and response to treatment in a variety of tumor types, but it remains unclear whether or not CIMP is a universal phenomenon across human neoplasia or if there should be cancer-specific definitions of the phenotype. Recently, it was shown that somatic isocitrate dehydrogenase-1 (IDH1) mutations, frequently observed in gliomas, establish CIMP in primary human astrocytes by remodeling the methylome. Interestingly, somatic IDH1 and IDH2 mutations, and loss-of-function mutations in ten-eleven translocation (TET) methylcytosine dioxygenase-2 (TET2) associated with a hypermethylation phenotype, are also found in multiple enchondromas of patients with Ollier disease and Mafucci syndrome, and leukemia, respectively. These data provide the first clues for the elucidation of a molecular basis for CIMP. Although CIMP appears as a phenomenon that occurs in various cancer types, the definition is poorly defined and differs for each tumor. The current perspective discusses the use of the term CIMP in cancer, its significance in clinical practice, and future directions that may aid in identifying the true cause and definition of CIMP in different forms of human neoplasia. Cancer Res; 73(19); 5858-68. Ó2013 AACR.

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“…The term CpG island methylator phenotype (CIMP) refers to the concordant occurrence of consistently increased methylation in multiple genes. This putative phenotype was first described in colon cancer (3) and subsequently in other tumors, such as those of the gastrointestinal tract (4 -7), nervous (8,9), and hematopoetic systems (10,11). Several studies associated CIMP with specific somatic genetic alterations, such as KRAS or BRAF mutations in colorectal cancer (12,13) and MYCN amplification in neuroblastomas (8,14).…”

mentioning

confidence: 99%

“…This putative phenotype was first described in colon cancer (3) and subsequently in other tumors, such as those of the gastrointestinal tract (4 -7), nervous (8,9), and hematopoetic systems (10,11). Several studies associated CIMP with specific somatic genetic alterations, such as KRAS or BRAF mutations in colorectal cancer (12,13) and MYCN amplification in neuroblastomas (8,14). Moreover, some observations also suggested generally increased cancer prevalence among firstgrade relatives to patients diagnosed with CIMP-positive colonic lesions (15,16).…”

mentioning

confidence: 99%

Global and Regional CpG Methylation in Pheochromocytomas and Abdominal Paragangliomas: Association to Malignant Behavior

Geli

Kiss

Karimi

et al. 2008

Clinical Cancer Research

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Purpose: This study aims to quantitatively assess promoter and global methylation changes in pheochromocytomas and abdominal paragangliomas and its relation to tumor phenotypes. Experimental Design: A panel of 53 primary tumors (42 benign, 11malignant) was analyzed by quantitative bisulfite pyrosequencing. Based on methylation levels in the tumor suppressor genes, p16 INK4A, CDH1, DCR2, RARB, RASSF1A, NORE1A,TP73, APC, DAPK1, p14 ARF , and PTEN, a CpG island methylator phenotype (CIMP) was defined as concerted hypermethylation in three or more genes. Mean Z scores for the hypermethylated promoters were calculated to characterize overall promoter methylation. Global DNA methylation was quantified for LINE-1 promoter sequences and by using luminescent methylation analysis. Results: Five primary tumors (9.4%) exhibited a CIMP phenotype, four of which were malignant paragangliomas. CIMP was significantly associated with malignant behavior (P = 0.005) and younger age at presentation (P < 0.007) but did not result from BRAF V600E mutation. Global hypomethylation of LINE-1 elements was observed in tumors compared with normal adrenal samples (P < 0.02). Conclusion:We here describe the identification of CIMP in abdominal paragangliomas and a strong association of this phenotype with malignant behavior, as well as young age at presentation. The findings raise a prospective for potential benefits of epigenetically acting drugs for a subgroup of young abdominal paraganglioma patients with adverse prognosis.

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Marked and independent prognostic significance of the CpG island methylator phenotype in neuroblastomas

Cited by 47 publications

References 16 publications

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

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

The CpG Island Methylator Phenotype: What's in a Name?

Global and Regional CpG Methylation in Pheochromocytomas and Abdominal Paragangliomas: Association to Malignant Behavior

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