CpG Island Methylation of Tumor-Related Promoters Occurs Preferentially in Undifferentiated Carcinoma

Schagdarsurengin, Undraga; Gimm, Oliver; Dralle, Henning; Hoang‐Vu, Cuong; Dammann, Reinhard

doi:10.1089/thy.2006.16.633

Cited by 91 publications

(101 citation statements)

References 31 publications

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“…This evolution is confirmed by several other facts: the aneuploidy, the generality of p53-inactivating mutations, both irreversible, and the complete loss of expression of differentiation genes in all the cell lines but not in FTCs or PTCs in vivo. Moreover, CpG island methylation of promoters is higher in cell lines than in differentiated carcinomas, and such profiles are different between different types of carcinomas and between these and their derived cell lines (41). This does not imply that the cell lines have lost all the characteristics of the original cancers; for example, they retain the causal oncogenic event BRAF activation for the B-CPAP cell line (42) and RET/PTC1 rearrangement for the TPC-1 cells (43), as well as the expression of thyroid-specific transcription factors.…”

Section: Resultsmentioning

confidence: 99%

Human Thyroid Tumor Cell Lines Derived from Different Tumor Types Present a Common Dedifferentiated Phenotype

Staveren¹,

Solís²,

Delys³

et al. 2007

Cancer Research

107

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Cell lines are crucial to elucidate mechanisms of tumorigenesis and serve as tools for cancer treatment screenings. Therefore, careful validation of whether these models have conserved properties of in vivo tumors is highly important. Thyrocyte-derived tumors are very interesting for cancer biology studies because from one cell type, at least five histologically characterized different benign and malignant tumor types can arise. To investigate whether thyroid tumorderived cell lines are representative in vitro models, characteristics of eight of those cell lines were investigated with microarrays, differentiation markers, and karyotyping. Our results indicate that these cell lines derived from differentiated and undifferentiated tumor types have evolved in vitro into similar phenotypes with gene expression profiles the closest to in vivo undifferentiated tumors. Accordingly, the absence of expression of most thyrocyte-specific genes, the nonresponsiveness to thyrotropin, as well as their large number of chromosomal abnormalities, suggest that these cell lines have acquired characteristics of fully dedifferentiated cells. They represent the outcome of an adaptation and evolution in vitro, which questions the reliability of these cell lines as models for differentiated tumors. However, they may represent useful models for undifferentiated cancers, and by their comparison with differentiated cells, can help to define the genes involved in the differentiation/dedifferentiation process. The use of any cell line as a model for a cancer therefore requires prior careful and thorough validation for the investigated property. [Cancer Res 2007;67(17):8113-20]

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Section: Resultsmentioning

confidence: 99%

Human Thyroid Tumor Cell Lines Derived from Different Tumor Types Present a Common Dedifferentiated Phenotype

Staveren¹,

Solís²,

Delys³

et al. 2007

Cancer Research

107

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“…Previous works demonstrate (48) that MEN1 promoter methylation can occur in pancreatic tumours, evidencing MEN1 as a methylation-prone tumour suppressor gene. The consequence of CpG island hypermethylation is down-regulation of gene expression and it has been shown to function as a second hit event that leads to biallelic inactivation in some tumour suppressor genes (49,50,51,52). Methylation of genes involved in parathyroid tumorigenesis has not been extensively studied, and the role of MEN1 CpG hypermethylation remains to be clarified.…”

Section: Discussionmentioning

confidence: 99%

MEN1 intragenic deletions may represent the most prevalent somatic event in sporadic primary hyperparathyroidism

Alvelos

Vinagre

Fonseca

et al. 2013

European Journal of Endocrinology

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Objective: Primary hyperparathyroidism (pHPT) is characterised by an inappropriate over production of parathyroid hormone and it is the most frequent pathological condition of the parathyroid glands. A minority of the cases belong to familial forms, but most of them are sporadic. The genetic alterations underlying the sporadic forms of pHPT remain poorly understood. The main goal of our study is to perform the molecular characterisation of a series of sporadic pHPT cases. Design and methods: We have studied matched blood and tumour from 24 patients with pHPT, who went to a medical appointment in Hospital Pedro Hispano. Informed consent was obtained from all individuals. The MEN1, RET and CDKN1B molecular study was carried out in the germline DNA by PCR/SSCP and direct sequencing. Parathyroid tumours were further analysed by the same methods for MEN1, CDKN1B and CTNNB1 genetic alterations. The multiplex ligation-dependent probe amplification technique enabled the evaluation of MEN1 gene deletions. Protein expression for menin, cyclin D1, parafibromin, p27Kip1 , b-catenin and Ki-67 was conducted by immunohistochemistry. Results: The study of parathyroid tumours detected two somatic MEN1 mutations (c.249_252delGTCT and c.115_163del49bp) and revealed the presence of MEN1 intragenic deletions in 54% (13/24) of the tumours. In RET and CDKN1B genes only previously described, non-pathogenic variants were found. Cyclin D1 protein was overexpressed in 13% (3/24) of tumours. Conclusions: These results suggest that MEN1 alterations, remarkably intragenic deletions, may represent the most prevalent genetic alteration in sporadic parathyroid tumours.

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“…Each tumor was scored based on the current TNM classification (19 (Table IV). Therefore, bisulfite-treated DNA samples were amplified with methylation-and unmethylation specific primers by a standard PCR protocol (20,21). All PCR products were analyzed on 2% TBE agarose gels.…”

Section: Methodsmentioning

confidence: 99%

Frequent promoter hypermethylation of tumor-related genes in head and neck squamous cell carcinoma

Steinmann

Sandner²,

Schagdarsurengin³

et al. 2009

Oncol Rep

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Abstract. Squamous cell carcinomas of head and neck (HNSCC) are a result of multiple genetic and epigenetic alterations. Epigenetic inactivation of tumor suppressor genes is an important event in head and neck carcinogenesis. Here we analyzed the promoter methylation of 15 genes (RASSF1A, p16, MGMT, DAPK, RARß, MLH1, CDH1, GSTP1, RASSF2, RASSF4, RASSF5, MST1, MST2, LATS1, LATS2) in 54 HNSCC and in matching 23 normal tissues. Methylation of these tumor-related genes (TRG) was significantly more frequent in HNSCC (42%) compared to normal samples (23%; p<0.05). Particularly, methylation of p16 (60%), MGMT (53%), DAPK (67%), RARß (75%), MLH1 (69%), CDH1 (43%), RASSF5 and MST1 (96%) was often found in HNSCC. Methylation of RASSF1A (18%), GSTP1 (4%), RASSF4 (13%), MST2 (4%), LATS1 (24%) and LATS2 (8%) was less frequently detected. A trend of increased TRG methylation in more advanced tumor stages and less differentiated HNSCC was observed. Methylation of p16 was significantly higher in poorly differentiated HNSCC (p=0.037) and RASSF5 methylation occurred preferentially in advanced tumor stages (p<0.05). Methylation of RASSF4 was higher in patients with recurrent HNSCC (23%) than patients without relapse (0%; p=0.033). Methylation of TRG in head and neck cancer cell lines was observed at similar frequency as in primary HNSCC. In summary, frequent hypermethylation of tumor-related genes in HNSCC was detected and this epigenetic silencing event may have an essential role in head and neck carcinogenesis.

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CpG Island Methylation of Tumor-Related Promoters Occurs Preferentially in Undifferentiated Carcinoma

Abstract: Our results show that hypermethylation of several tumor-related gene promoters is a frequent event in UTC. The hypermethylation status may be reversed by DNA demethylating agents. Their clinical value remains to be investigated.

Cited by 91 publications

References 31 publications

Human Thyroid Tumor Cell Lines Derived from Different Tumor Types Present a Common Dedifferentiated Phenotype

Human Thyroid Tumor Cell Lines Derived from Different Tumor Types Present a Common Dedifferentiated Phenotype

MEN1 intragenic deletions may represent the most prevalent somatic event in sporadic primary hyperparathyroidism

Frequent promoter hypermethylation of tumor-related genes in head and neck squamous cell carcinoma

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