Altered methylation of multiple genes in carcinogenesis of the prostate

Yamanaka, Masamichi; Watanabe, Masatoshi; Yumura, Yasushi; Takagi, Akimitsu; Murata, Tetsuya; Takahashi, Hiroyuki; Suzuki, Hiroyoshi; Itô, Haruo; Tsukino, Hiromasa; Katoh, Takahiko; Sugimura, Yoshiki; Shiraishi, Taizo

doi:10.1002/ijc.11227

Cited by 113 publications

(125 citation statements)

References 38 publications

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“…Consistent with our results, other studies have also described quantitatively much less promoter methylation of GSTP1 in BPH and histologically normal tissue (from tumour containing prostates) than in cancer specimens (Jeronimo et al, 2001;Yamanaka et al, 2003). Although every effort was taken to ensure that tissue was only procured from within pathologically identified areas, we cannot rule out the possibility that minute amounts of occult carcinoma or HGPIN may have been present in some of the benign specimens.…”

Section: Discussionsupporting

confidence: 90%

In silico mining identifies IGFBP3 as a novel target of methylation in prostate cancer

et al. 2007

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Promoter hypermethylation is central in deregulating gene expression in cancer. Identification of novel methylation targets in specific cancers provides a basis for their use as biomarkers of disease occurrence and progression. We developed an in silico strategy to globally identify potential targets of promoter hypermethylation in prostate cancer by screening for 5 0 CpG islands in 631 genes that were reported as downregulated in prostate cancer. A virtual archive of 338 potential targets of methylation was produced. One candidate, IGFBP3, was selected for investigation, along with glutathione-S-transferase pi (GSTP1), a well-known methylation target in prostate cancer. Methylation of IGFBP3 was detected by quantitative methylation-specific PCR in 49/79 primary prostate adenocarcinoma and 7/14 adjacent preinvasive high-grade prostatic intraepithelial neoplasia, but in only 5/37 benign prostatic hyperplasia (Po0.0001) and in 0/39 histologically normal adjacent prostate tissue, which implies that methylation of IGFBP3 may be involved in the early stages of prostate cancer development. Hypermethylation of IGFBP3 was only detected in samples that also demonstrated methylation of GSTP1 and was also correlated with Gleason score X7 (P ¼ 0.01), indicating that it has potential as a prognostic marker. In addition, pharmacological demethylation induced strong expression of IGFBP3 in LNCaP prostate cancer cells. Our concept of a methylation candidate gene bank was successful in identifying a novel target of frequent hypermethylation in earlystage prostate cancer. Evaluation of further relevant genes could contribute towards a methylation signature of this disease.

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Section: Discussionsupporting

confidence: 90%

In silico mining identifies IGFBP3 as a novel target of methylation in prostate cancer

et al. 2007

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“…Previous studies showed that HIC-1 was commonly hypermethylated and transcriptionally inactivated in leukemia, medulloblastoma, and cancers of breast, prostate, and uterine cervix. 23,[41][42][43][44] In the present study, HIC-1 was the most frequently methylated gene among the panel of genes studied in both hydatidiform moles as well as in choriocarcinoma. This indicated that methylation of HIC-1 might be an early event involved in the pathogenesis of GTD.…”

Section: Figurementioning

confidence: 83%

Promoter Hypermethylation of Multiple Genes in Hydatidiform Mole and Choriocarcinoma

Xue

Chan

Feng

et al. 2004

The Journal of Molecular Diagnostics

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The methylation status of genes in hydatidiform mole and choriocarcinoma and its significance is relatively unexplored. We investigated the methylation status of the promoter regions of six genes, p16, HIC-1, TIMP3, GSTP1, death-associated protein kinase (DAPK), and E-cadherin in 54 hydatidiform moles, five choriocarcinomas, and 10 first trimester placenta by methylation-specific polymerase chain reaction (PCR). Immunohistochemical expression of p16, TIMP3, and E-cadherin, and quantitative real-time RT-PCR of p16 was also performed. Among the six genes examined, the promoter region of four genes (E-cadherin, HIC-1, p16, TIMP3) in choriocarcinoma and three genes (E-cadherin, HIC-1, p16) in hydatidiform mole exhibited aberrant methylation whereas none was hypermethylated in normal placenta. There was a significant correlation between methylation and reduced expression of p16, E-cadherin, and TIMP3 (P < 0.001). Fifteen of the 54 patients with hydatidiform mole developed gestational trophoblastic neoplasia requiring chemotherapy. Promoter hypermethylation of p16 alone, or combined with E-cadherin, was significantly correlated to such development (P ‫؍‬ 0.001, 0.0005, respectively). Hypermethylation of multiple genes, especially p16, might be related to the subsequent development of gestational trophoblastic neoplasia. (J Mol Diagn 2004, 6:326 -334)

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“…DNA methylation patterns in CpG islands of tumor suppressor genes p16 (20), BRCA1 (21), RASSF1A (22), ER-␣ (23), TMS1 (24), TIMP and GSTP1 (25), Twist (26), AR (27), and hMLH1 (28) were determined by chemical modification with sodium bisulfite. The primer sequences used have all been reported previously and can be found in the report referenced after each gene.…”

Section: Methodsmentioning

confidence: 99%

The Contribution of Genetic and Epigenetic Changes in Granulosa Cell Tumors of Ovarian Origin

Dhillon

Aslam

Husain

2004

Clinical Cancer Research

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Purpose: Granulosa cell tumors (GCTs) are relatively rare and are subtypes of the sex-cord stromal neoplasms. A better understanding of the molecular genetics underlying various steps in malignant transformation is critical to success in the battle against this disease. Changes in the status of methylation, known as epigenetic alterations, are one of the most common molecular alterations in human cancers, including GCTs. Chromosomal instability and microsatellite instability (MSI) are common in these GCTs. We tested the hypothesis that C3 T transition polymorphism in the promoter region of cytosine DNA-methyltransferase-3B (DNMT3B) and its altered expression are also associated with hypermethylation of the genes. We also attempted to determine the relationship between MSI of ovarian carcinoma and hMLH1 hypermethylation in these tumors.Experimental Design: We studied chromosome instability in 25 GCTs by detecting gross chromosome rearrangements in cultured peripheral blood lymphocytes. MSI was assessed using six microsatellite markers (BAT25, BAT26, D2S123, D5S346, D11S1318, and D17S250). Using sensitive methylation-specific PCR, we searched for aberrant promoter hypermethylation in a panel of genes including p16, BRCA1, RASSF1A, ER-␣, TMS1, TIMP3, Twist, GSTP1, AR, and hMLH1. Polymorphism in the DNMT3B gene was assessed by the PCR-RFLP method, and DNMT3B expression was studied by reverse transcription-PCR assay.Results: Chromosome instability was indicated by significantly higher frequencies of chromosome aberrations (6.24%; P < 0.001) compared with controls (2.12%). The most frequently observed changes include trisomy 14 and monosomy 22. MSI has been found in 19 of 25 tumors, and loss of heterozygosity has been found in 9 of 25 tumors. Frequencies of methylation in GCTs were 40% for p16 and ER-␣; 36% for BRCA1 and RASSF1A; 28% for hMLH1; 24% for TIMP3, Twist, and GSTP1; and 20% in TMS1 and AR. TT genotype was found only in two cases; the remainder were either CC or CT type. There was no significant alteration in the expression of DNMT3B in these patients.Conclusions: Coexistence of chromosome instability, MSI, and hypermethylation suggests that both genetic and epigenetic mechanisms may act in concert to inactivate the above-mentioned genes in these GCTs. These mechanisms can be an early event in the pathogenesis of these tumors, and it can be a critical step in the tumorigenic process. All these events might play an important role in early clinical diagnosis and in chemotherapeutic management and treatment of the disease. Larger studies may lend further understanding to the etiology and clinical behavior of these tumors.

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Altered methylation of multiple genes in carcinogenesis of the prostate

Cited by 113 publications

References 38 publications

In silico mining identifies IGFBP3 as a novel target of methylation in prostate cancer

In silico mining identifies IGFBP3 as a novel target of methylation in prostate cancer

Promoter Hypermethylation of Multiple Genes in Hydatidiform Mole and Choriocarcinoma

The Contribution of Genetic and Epigenetic Changes in Granulosa Cell Tumors of Ovarian Origin

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