Aneuploidy of Chromosome 9 and the Tumor Suppressor Genes p16&lt;sup&gt;INK4&lt;/sup&gt; and p15&lt;sup&gt;INK4B&lt;/sup&gt; Detected by in situ Hybridization in Locally Advanced Prostate Cancer

Heidenreich, Birgit; Heidenreich, Axel; Sesterhenn, Andreas M.; Srivastava, Shiv; Moul, Judd W.; Sesterhenn, Isabell A.

doi:10.1159/000020327

Cited by 16 publications

(10 citation statements)

References 25 publications

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“…PIN is frequently found adjacent to prostate cancer in total prostatectomy specimens and is considered to be a premalignant lesion. Many studies have reported that many genetic changes found in prostate cancer also occur in PIN 8, 21–23. The present study demonstrates CpG island hypermethylation of multiple genes in PIN, although the number of genes methylated and the methylation frequency of specific genes were lower in PIN than in prostate cancer.…”

Section: Discussionsupporting

confidence: 47%

Aberrant CpG island hypermethylation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia

Kang

Lee

et al. 2004

The Journal of Pathology

219

226

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To date, several reports have been published about CpG island methylation of various genes in prostate cancer. However, most of these studies have focused on cancer tissue only or a single gene and data about concurrent methylation of multiple genes in prostate cancer or prostatic intraepithelial neoplasia (PIN) are limited. The aim of the present study was to determine the methylation profile of 11 tumour-related genes in prostate cancer and PIN. Seventy-one samples, including 37 prostate cancers, 14 PINs, and 20 normal prostates, were examined for the methylation status of 11 tumour-related genes using methylation-specific PCR. The mean number of genes methylated was significantly higher in prostate cancer and PIN than in non-neoplastic prostate (4.4, 3, and 0.2, respectively; p < 0.001). In prostate cancer, APC, GSTP1, MGMT, and RASSF1A were frequently methylated at a frequency of 56.8%, 86.5%, 75.7%, and 83.8%, respectively. These genes were methylated in more than 30% of PINs. Prostate cancers with high serum prostate-specific antigen (PSA) (more than 8 ng/ml) or a high Gleason score (GS) (3 + 4 or more) showed higher numbers of methylated genes than those with low serum PSA (8 or less) or low GS (3 + 3 or less) (5.4 versus 2.5 and 5.4 versus 3.1, respectively; p < 0.05). The methylation frequency of APC, RASSF1A, and RUNX3 was higher in prostate cancers with high serum PSA or with high GS than in those with low PSA or with low GS, respectively, the differences reaching statistical significance (p < 0.05). A strong association between MGMT methylation and loss of MGMT expression was demonstrated by immunohistochemistry. CpG island methylation is a frequent event, occurs early, and accumulates during multi-step prostatic carcinogenesis. High levels of CpG island hypermethylation might serve as a potential biological marker for aggressive prostate cancer.

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Section: Discussionsupporting

confidence: 47%

Aberrant CpG island hypermethylation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia

Kang

Lee

et al. 2004

The Journal of Pathology

219

226

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“…In fact, chromosome 21 also has a greater than twofold enrichment of aberrant compartmentalization (a full table of ratios of observed/expected numbers of aberrantly compartmentalized windows for each chromosome is given in Additional file 4). This chromosomal enrichment of aberrantly compartmentalized windows is very similar for both tumour-specific open chromatin and tumour-specific closed chromatin and may arise from epigenetic changes linked to frequent aneuploidy events [18]. …”

Section: Resultsmentioning

confidence: 99%

DNA methylation-based chromatin compartments and ChIP-seq profiles reveal transcriptional drivers of prostate carcinogenesis

2017

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BackgroundProfiles of DNA methylation of many tissues relevant in human disease have been obtained from microarrays and are publicly available. These can be used to generate maps of chromatin compartmentalization, demarcating open and closed chromatin across the genome. Additionally, large sets of genome-wide transcription factor binding profiles have been made available thanks to ChIP-seq technology.MethodsWe have identified genomic regions with altered chromatin compartmentalization in prostate adenocarcinoma tissue relative to normal prostate tissue, using DNA methylation microarray data from The Cancer Genome Atlas. DNA binding profiles from the Encyclopedia of DNA Elements (ENCODE) ChIP-seq studies have been systematically screened to find transcription factors with inferred DNA binding sites located in discordantly open/closed chromatin in malignant tissue (compared with non-cancer control tissue). We have combined this with tests for corresponding up-/downregulation of the transcription factors’ putative target genes to obtain an integrated measure of cancer-specific regulatory activity to identify likely transcriptional drivers of prostate cancer.ResultsGenerally, we find that the degree to which transcription factors preferentially bind regions of chromatin that become more accessible during prostate carcinogenesis is significantly associated to the level of systematic upregulation of their targets, at the level of gene expression. Our approach has yielded 11 transcription factors that show strong cancer-specific transcriptional activation of targets, including the novel candidates KAT2A and TRIM28, alongside established drivers of prostate cancer MYC, ETS1, GABP and YY1.ConclusionsThis approach to integrated epigenetic and transcriptional profiling using publicly available data represents a cheap and powerful technique for identifying potential drivers of human disease. In our application to prostate adenocarcinoma data, the fact that well-known drivers are amongst the top candidates suggests that the discovery of novel candidate drivers may unlock pathways to future medicines.Data download instructions and code to reproduce this work are available at GitHub under ‘edcurry/PRAD-compartments’.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0443-z) contains supplementary material, which is available to authorized users.

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“…Finally, the role of p16 ink4a remains an enigma. While p16 ink4a shows clear tumor suppressor function in a number of tissue types, p16 ink4a levels in prostate cancer show a wide range of expression (Cairns et al, 1995; Chakravarti et al, 2007, 2003; Chen et al, 1996; Chi et al, 1997; Cho et al, 2007; Faith et al, 2005; Gu et al, 1998; Halvorsen et al, 2000; Heidenreich et al, 2000; Henshall et al, 2001; Iemely-nova et al, 2009; Jarrard et al, 1997, 2002; Jeronimo et al, 2004; Komiya et al, 1995; Konishi et al, 2002; Lee et al, 1999; Maruyama et al, 2002; Nguyen et al, 2000; Perinchery et al, 1999; Roach et al, 2009; Tamimi et al, 1996; Zhang et al, 2006). Moreover, no clear patterns of associated clinical correlates have emerged from studies to date.…”

Section: Clinical Relevance Of Cell Cycle-ar Crosstalkmentioning

confidence: 99%

The AR dependent cell cycle: Mechanisms and cancer relevance

Schiewer

Augello

Knudsen

2012

Molecular and Cellular Endocrinology

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Prostate cancer cells are exquisitely dependent on androgen receptor (AR) activity for proliferation and survival. As these functions are critical targets of therapeutic intervention for human disease, it is imperative to delineate the mechanisms by which AR engages the cell cycle engine. More than a decade of research has revealed that elegant intercommunication between AR and the cell cycle machinery governs receptor-dependent cellular proliferation, and that perturbations in this process occur frequently in human disease. Here, AR–cell cycle interplay and associated cancer relevance will be reviewed.

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Aneuploidy of Chromosome 9 and the Tumor Suppressor Genes p16<sup>INK4</sup> and p15<sup>INK4B</sup> Detected by in situ Hybridization in Locally Advanced Prostate Cancer

Cited by 16 publications

References 25 publications

Aberrant CpG island hypermethylation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia

Aberrant CpG island hypermethylation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia

DNA methylation-based chromatin compartments and ChIP-seq profiles reveal transcriptional drivers of prostate carcinogenesis

The AR dependent cell cycle: Mechanisms and cancer relevance

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