Quantitative, spatial resolution of the epigenetic field effect in prostate cancer

Mehrotra, Jyoti; Varde, Shobha; Wang, Haiying; Chiu, Hsiling; Vargo, Janet M.; Gray, Karen; Nagle, Raymond B.; Neri, Jaclyn R.; Mazumder, Abhijit

doi:10.1002/pros.20675

Cited by 65 publications

(62 citation statements)

References 20 publications

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“…In contrast, few expression studies have reported molecular signatures and individual markers characteristic of prostatic TAHN tissues. Field cancerization is however evident at the genetic as well as the epigenetic level, as we have shown by altered telomeres in whole tissue TAHN extracts (11) and as shown by others by gene promoter methylation of APC, RARß2 and RASSF1A (34). Field cancerization in prostatic tissues is also evidenced by RNA/ protein expression analysis (35,36).…”

Section: Discussionsupporting

confidence: 60%

Differential gene expression in tumor adjacent histologically normal prostatic tissue indicates field cancerization

Haaland

Heaphy²,

Butler³

et al. 2009

Int J Oncol

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Abstract. Field cancerization denotes the occurrence of aberrant cells in tumor adjacent histologically normal tissues (TAHN). To characterize field cancerization in prostate cancer, we used RNA from paired patient tumor and TAHN tissues excised at 1 cm from the tumor margin and subjected them to microarray expression analysis comparative to RNA from normal cancer-free prostatic tissues. Eleven novel transcripts were significantly up-regulated in TAHN tissues and also in tumors. Expression of early growth response protein 1, tristetraprolin, testican, and fatty acid synthase, mutually up-regulated at different levels in tumors and TAHN tissues was confirmed by quantitative reverse transcriptase PCR in the experimental and in an independent validation set. This study offers proof of expressional changes in field cancerized prostatic TAHN tissues at defined distances from tumor margins. Markers of field cancerized prostatic tissues could be early diagnostic indicators in biopsies after abnormal prostate-specific antigen and digital rectal examination and independent of cancerous histology and/or early targets for chemo-preventive intervention in pre-malignant disease.

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Section: Discussionsupporting

confidence: 60%

Differential gene expression in tumor adjacent histologically normal prostatic tissue indicates field cancerization

Haaland

Heaphy²,

Butler³

et al. 2009

Int J Oncol

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“…Although some of the above mentioned genes were already investigated in PCa, the results are sometimes contradictory [17,18] . Therefore, we analyzed tumor and tumor-adjacent tissues of a set of well-characterized prostatectomy specimens for a putative methylation field effect, which may be an indicator for PCa even in histologically tumor-free tissue.…”

mentioning

confidence: 99%

Gene Promoter Methylation and Its Potential Relevance in Early Prostate Cancer Diagnosis

Steiner

Jung²,

Schatz³

et al. 2010

Pathobiology

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Aims: We investigated hypermethylation of the glutathione S-transferase pi (GSTP1), retinoic acid receptor β2 (RARβ2), adenomatous polyposis coli (APC) and paired-like homeodomain transcription factor 2 (PITX2) gene promoters which could serve as a sensitive tool to indicate a risk of prostate cancer even in histologically tumor-free tissues. Methods: Tumor tissues and non-neoplastic tissues at variable distances from the tumor foci were retrieved from 25 formalin-fixed and paraffin-embedded prostatectomy specimens and subjected to DNA extraction. The methylation levels were assessed by means of different assay technologies. Results: Significantly increased methylation levels in cancer specimens were found for all promoter regions (GSTP1: 21/25, 84%; RARβ2: 24/25, 96%; APC: 21/25, 84%; PITX2: 20/25, 80%) and in most samples containing prostatic intraepithelial neoplasia. Several samples showed increased RARβ2 and APC methylation in adjacent non-neoplastic tissue. An association between the methylation extent of GSTP1, APC and RARβ2, respectively, and primary Gleason grade was detectable. GSTP1 methylation was also associated with extraprostatic tumor extension. Conclusion: GSTP1, APC, RARβ2 and PITX2 methylation occur frequently in prostate cancer, making these markers sensitive tools for the detection of neoplastic lesions in the prostate. For RARβ2, the results suggest a kind of methylation field effect which could be helpful for the detection of prostate cancer. Larger studies are necessary to investigate a potential correlation of GSTP1, RARβ2 and APC hypermethylation with tumor aggressiveness.

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“…A number of investigators have confirmed the concept of precancerous molecular events in normal-appearing cells using different markers. [11][12][13] The obvious benefit of such field biomarkers is in the selection of men at high risk of cancer for close monitoring, while reassuring the low-risk population.…”

Section: Discussionmentioning

confidence: 99%

“…Several groups have confirmed field cancer effects in prostatic tissues. 12,15,16 Chemoprevention or early detection strategies would benefit from the profiling of cancer field biomarkers in high-risk populations. A histologically normal surgical margin may warrant molecular examination to preclude submicroscopic involvement.…”

Section: Discussionmentioning

confidence: 99%

Accurate prediction of repeat prostate biopsy outcomes by a mitochondrial DNA deletion assay

Robinson¹,

Creed²,

Reguly³

et al. 2010

Prostate Cancer Prostatic Dis

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Several cancers are characterized by large-scale mtDNA deletions. We previously provided evidence that one of these deletions has potential utility in resolving false from true-negative prostate needle biopsies. This study was to assess the clinical value of this deletion in predicting re-biopsy outcomes. We used a quantitative polymerase chain reaction assay to measure the levels of the deletion in individual negative needle biopsies from 101 patients who had a repeat biopsy within a year with known outcomes. Using an empirically established cycle threshold (Ct) cutoff of 31, and the lowest Ct for each patient as diagnostic of prostate cancer, as well as the histopathologic diagnosis on second biopsy, we calculated the clinical performance of the deletion. The Ct cutoff at 31 gave a sensitivity and specificity of 84 and 54%, respectively, with the area under a receiver-operating characteristics curve of 0.749. The negative predictive value was 91%. The assay was able to predict the presence of a missed tumor in 17 out of 20 men a year before diagnosis. This ancillary test appears to identify men who do not require a repeat biopsy with a high degree of certainty. The results suggest that the majority of men with atypical small acinar proliferation have a concurrent missed tumor and therefore require close monitoring for early detection.

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Quantitative, spatial resolution of the epigenetic field effect in prostate cancer

Cited by 65 publications

References 20 publications

Differential gene expression in tumor adjacent histologically normal prostatic tissue indicates field cancerization

Differential gene expression in tumor adjacent histologically normal prostatic tissue indicates field cancerization

Gene Promoter Methylation and Its Potential Relevance in Early Prostate Cancer Diagnosis

Accurate prediction of repeat prostate biopsy outcomes by a mitochondrial DNA deletion assay

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