DNA Methylation-Guided Prediction of Clinical Failure in High-Risk Prostate Cancer

Litovkin, Kirill; Eynde, Aleyde Van; Joniau, Steven; Lerut, Evelyne; Laenen, Annouschka; Gevaert, Thomas; Gevaert, Olivier; Spahn, Martin; Kneitz, Burkhard; Gramme, Pierre; Helleputte, Thibault; Isebaert, Sofie; Haustermans, Karin; Bollen, Mathieu

doi:10.1371/journal.pone.0130651

Cited by 30 publications

(26 citation statements)

References 59 publications

(72 reference statements)

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“…This potential role for APC , GSTM2 and RARβ is already known [7,11,22,23,] but ALOX12 , MT1A and MYCL2 methylation are novel potential biomarkers that merit further validation. Identification of new methylation markers could depend on the population studied itself.…”

Section: Discussionmentioning

confidence: 89%

“…In recent years, other variable DNA methylation alterations in neoplastic tissue samples have been also associated with the prediction of PSA recurrence after RP [10,17,18,19,20,21,22,23,24]. These studies have identified new potential tumor markers including methylation of PITX2 , HOXD3 , APC , TGFβ2 , RASSF1A , ANEP , PCDH10 , ZNF132 , TDRD1 , AOX1 , C1orf114 , GAS6 , HAPLN3 , KLF8 , MOB3B , CCND2 , PTGS2 , RARB , SRD5A2 and CYP11A1 , thus emerging as new predictors of BCR particularly in high-risk clinically localized disease.…”

Section: Discussionmentioning

confidence: 99%

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A DNA Hypermethylation Profile Independently Predicts Biochemical Recurrence Following Radical Prostatectomy

Angulo

López

Dorado³

et al. 2016

Urol Int

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Purpose: Detection of DNA hypermethylation is emerging as a novel molecular biomarker for different malignancies. We intend to define whether a hypermethylation profile of patients with prostate cancer (PCa) predicts biochemical recurrence (BCR) after radical prostatectomy (RP). Material and Methods: Genome-wide methylation analysis was performed using the GoldenGate Methylation Cancer Panel-I (Illumina, Inc.) on 10 normal prostate tissues and 58 tumor samples from patients treated by RP followed for prostate-specific antigen (PSA) failure (>0.4 ng/ml) and disease progression. Patients were classified on the basis of D'Amico criteria according to clinical staging, PSA at diagnosis and Gleason score after pathologist review. Hypermethylation status of 1505 CpGs present in the promoter region of 807 genes was studied. Hierarchical clustering analysis was performed and relationships with outcome were investigated using log-rank analysis and Cox regression model. Results: We found 28 genes significantly hypermethylated in >20% of the tumors analyzed. Four clusters of patients were characterized by their DNA methylation profile, one at higher risk to develop BCR (p = 0.005). Multivariate analysis revealed patients in this cluster (HR 2.56), and high-risk patients (HR 4.34) according to D'Amico classification were independent predictors of BCR after prostatectomy. From the selected genes MT1A, ALOX12, GSTM2, APC, MYCL2 and RARB hypermethylation predicted BCR and GSTM2 (HR 3.78) and MYCL2 hypermethylation (HR 2.71) did so independently. Conclusion: Epigenetic silencing of GSTM2 and MYCL2 comprise novel molecular markers to predict BCR after surgery for medium- and high-risk localized PCa undergoing surgical treatment and hypermethylation of these genes could be incorporated to the clinical and pathological factors defining the patient at higher risk of PSA failure after prostatectomy. The limitation of the study is that no independent validation cohort is analysed.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

A DNA Hypermethylation Profile Independently Predicts Biochemical Recurrence Following Radical Prostatectomy

Angulo

López

Dorado³

et al. 2016

Urol Int

View full text Add to dashboard Cite

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“…Others have sought to relate CpG methylation patterns to clinical outcome and combined their patterns in univariate regression analyses of time to disease recurrence and revealed that methylation of certain loci, for example again including AOX1 and RARB [133] predicted disease progression [134,135]. Further supporting the relevance of DMR in PCa progression, the TCGA investigators revealed how altered DNA methylation patterns associated with different PCa genetic phenotypes.…”

Section: Prostate Cancer As a Model Of The Interplay Between Genommentioning

confidence: 99%

The Genomic Impact of DNA CpG Methylation on Gene Expression; Relationships in Prostate Cancer

2017

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The process of DNA CpG methylation has been extensively investigated for over 50 years and revealed associations between changing methylation status of CpG islands and gene expression. As a result, DNA CpG methylation is implicated in the control of gene expression in developmental and homeostasis processes, as well as being a cancer-driver mechanism. The development of genome-wide technologies and sophisticated statistical analytical approaches has ushered in an era of widespread analyses, for example in the cancer arena, of the relationships between altered DNA CpG methylation, gene expression, and tumor status. The remarkable increase in the volume of such genomic data, for example, through investigators from the Cancer Genome Atlas (TCGA), has allowed dissection of the relationships between DNA CpG methylation density and distribution, gene expression, and tumor outcome. In this manner, it is now possible to test that the genome-wide correlations are measurable between changes in DNA CpG methylation and gene expression. Perhaps surprisingly is that these associations can only be detected for hundreds, but not thousands, of genes, and the direction of the correlations are both positive and negative. This, perhaps, suggests that CpG methylation events in cancer systems can act as disease drivers but the effects are possibly more restricted than suspected. Additionally, the positive and negative correlations suggest direct and indirect events and an incomplete understanding. Within the prostate cancer TCGA cohort, we examined the relationships between expression of genes that control DNA methylation, known targets of DNA methylation and tumor status. This revealed that genes that control the synthesis of S-adenosyl-l-methionine (SAM) associate with altered expression of DNA methylation targets in a subset of aggressive tumors.

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“…In 65% of the cases, the treatment recommendation changed after the genetic test, and in 40% there was reduction in treatment burden (interventional treatment changed to noninterventional). Although this study shows genomic tests can have a significant impact on treatment decisions, follow-up data were not reported to determine the long-term impact of these changes in management [83]. In another study involving 149 prostate cancer patients, the promoter methylation of seven genes was evaluated by methylation-sensitive PCR in tissue and urine samples.…”

Section: • Methylation Assaysmentioning

confidence: 97%

Biomarkers in Localized Prostate Cancer

et al. 2016

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Biomarkers can improve prostate cancer diagnosis and treatment. Accuracy of prostatespecific antigen (PSA) for early diagnosis of prostate cancer is not satisfactory, as it is an organbut not cancer-specific biomarker, and it can be improved by using models that incorporate PSA along with other test results, such as prostate cancer antigen 3, the molecular forms of PSA (proPSA, benign PSA and intact PSA), as well as kallikreins. Recent reports suggest that new tools may be provided by metabolomic studies as shown by preliminary data on sarcosine. Additional molecular biomarkers have been identified by the use of genomics, proteomics and metabolomics. We review the most relevant biomarkers for early diagnosis and management of localized prostate cancer. KEYWORDS• biomarkers • prostate cancerThe European randomized study of screening for prostate cancer showed that prostate-specific antigen (PSA)-based screening in senior men was associated with a statistically significant 29% prostate cancer mortality reduction [1]. Nevertheless, as many as 40% of those screened are at risk to be treated for a biologically indolent disease that will not affect their life expectancy [1], which results in a 23% negative impact on the life-years gained [2]. The conclusion of one recently published cost-effectiveness analysis was that PSA-based screening should be limited to two or three screens between ages 55 and 59 years because in men older than 63 years overdiagnosis is responsible for loss of quality-adjusted life-years [3]. Several clinical, pathological and biological variables [4] were reported to improve the modest accuracy of PSA as a screening test, although their impact in a community-based setting is yet to be assessed in large trials. An analysis of six externally validated PSA-based models that incorporated readily available variables such as age, race, digital rectal examination, previous biopsies, family history, free PSA, transrectal ultrasonography prostate volume showed that five of these were able to double the sensitivity of PSA testing (44 vs 21%) without loss of specificity [5]. Furthermore, the Prostate Cancer Prevention Trial model can also predict the presence of Gleason ≥7 versus Gleason <7 prostate cancer [6]. Many novel biomarkers also provide valuable prognostic information that can have important therapeutic implications and serve as 400REviEW Ferro, Buonerba, Terracciano et al. future science group selection criteria for patients eligible for active surveillance or candidates for radiotherapy/surgery [7]. In this review, we will focus on the most relevant biomarkers potentially useful for prostate cancer early diagnosis and for assessment of the prognosis of localized disease. Evidence supporting the use of the biomarkers discussed is presented along with a critical analysis of their potential impact on future research and clinical practice. Serum biomarkersPSA is a glycoprotein serine protease that promotes sperm motility via degradation of the semenogelin I and II proteins [8]. In a landmark s...

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DNA Methylation-Guided Prediction of Clinical Failure in High-Risk Prostate Cancer

Cited by 30 publications

References 59 publications

A DNA Hypermethylation Profile Independently Predicts Biochemical Recurrence Following Radical Prostatectomy

A DNA Hypermethylation Profile Independently Predicts Biochemical Recurrence Following Radical Prostatectomy

The Genomic Impact of DNA CpG Methylation on Gene Expression; Relationships in Prostate Cancer

Biomarkers in Localized Prostate Cancer

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