DNA methylation of HOXD3 as a marker of prostate cancer progression

Kron, Ken J.; Liu, Liyang; Pethe, Vaijayanti; Demetrashvili, Nino; Nesbitt, Michael; Trachtenberg, John; Özçelik, Hilmi; Fleshner, Neil; Briollais, Laurent; Kwast, Theodorus H. van der; Bapat, Bharati

doi:10.1038/labinvest.2010.57

Cited by 51 publications

(65 citation statements)

References 46 publications

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“…Aberrations to DNA methylation in certain GP morphologies require further investigation as it may improve personalized patient treatment by utilizing biomarker information. The DNA methylation of APC, CYP26A1, HOXD3, HOXD8, RASSF1, TBX15 and TGFβ2 genes were investigated in the current study, as they have previously been revealed as promising prognostic biomarkers for PCa with the potential for clinical utility in independent patient cohorts (23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

“…DNA was extracted from 10 µm sections of previously prepared FFPE blocks matching the selected H&E slides using a QIAamp DNA Mini kit (Qiagen, Inc., Valencia, CA, USA), as previously described (23)(24)(25). DNA methylation was analyzed in the same GP4 area used for histological evaluation.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, a total of 100-400 ng extracted DNA from the GP4 region for each GS7 case was bisulfite modified using EZ DNA Methylation Gold kit (Zymo Research Corp, Irvine, CA, USA), according to the manufacturer's protocol. Methylated genes were detected using a MethyLight quantitative polymerase chain reaction (qPCR) assay that was conducted using the TaqMan ® Gold with Buffer A pack (Thermo Fisher Scientific, Inc., Waltham, MA, USA), as described previously (23)(24)(25). The primer and probe sequences are presented in Table II.…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, DNA methylation markers are emerging as promising biomarkers of prostate carcinogenesis, thus complementing, if not altogether avoiding, the requirement for the histopathological examination of biopsy tissue samples (22). The results of our previous studies demonstrated that the DNA hypermethylation of a panel of seven genes [adenomatous polyposis coli (APC), cytochrome P450 family 26 subfamily A member 1 (CYP26A1), homeobox D3 (HOXD3), HOXD8, Ras association domain family member 1 (RASSF1), T-box 15 (TBX15) and transforming growth factor-β2 (TGFβ2)] is associated with PCa disease progression and clinical outcome (23)(24)(25). These markers were initially identified through a genome-wide methylation screen of low-grade and high-grade PCas (23).…”

Section: Introductionmentioning

confidence: 99%

“…The results of our previous studies demonstrated that the DNA hypermethylation of a panel of seven genes [adenomatous polyposis coli (APC), cytochrome P450 family 26 subfamily A member 1 (CYP26A1), homeobox D3 (HOXD3), HOXD8, Ras association domain family member 1 (RASSF1), T-box 15 (TBX15) and transforming growth factor-β2 (TGFβ2)] is associated with PCa disease progression and clinical outcome (23)(24)(25). These markers were initially identified through a genome-wide methylation screen of low-grade and high-grade PCas (23). Subsequently, the prognostic potential of a subset of these markers was validated in an independent cohort (24,25).…”

Section: Introductionmentioning

confidence: 99%

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Distinct DNA methylation alterations are associated with cribriform architecture and intraductal carcinoma in Gleason pattern 4 prostate tumors

et al. 2017

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Abstract. The aim of the present study was to explore DNA methylation aberrations in association with cribriform architecture and intraductal carcinoma (IDC) of the prostate, as there is robust evidence that these morphological features are associated with aggressive disease and have significant clinical implications. Herein, the associations of a panel of seven known prognostic DNA methylation biomarkers with cribriform and IDC features were examined in a series of 91 Gleason pattern (GP) 4 tumors derived from Gleason score 7 radical prostatectomies. Gene specific DNA methylation was compared between cribriform and/or IDC positive vs. negative cases, and in association with clinicopathological features, using Chi square and Mann-Whitney U tests. DNA methylation of the adenomatous polyposis coli, Ras association domain family member 1 and T-box 15 genes was significantly elevated in GP4 tumors with cribriform and/or IDC features compared with negative cases (P=0.045, P=0.007 and P=0.013, respectively). To the best of our knowledge, this provides the first evidence for an association between cribriform and/or IDC and methylation biomarkers, and warrants further investigation of additional DNA methylation events in association with various architectural patterns in prostate cancer. IntroductionProstate cancer (PCa) is the second most common type of cancer affecting men worldwide, with an incidence of 1.1 million new cases each year (1). The most widely accepted pathological grading of PCa is the Gleason Score (GS), which is based on architectural features of the gland and is comprised of the sum of two Gleason Patterns (GP) (2). The GS grading system is among the most effective predictors of clinical outcomes following radical prostatectomy (RP), and is universally used to guide PCa treatment (3). Within this system, GS6 PCas are low grade, whereas GS8 or higher are classified as high grade. GS7 prostate adenocarcinomas consisting of variable proportions of GP3 and GP4 are considered to be intermediate grade, and represent the most heterogeneous group of neoplasms with diverse clinical outcomes (4,5) Thus, GS7 PCa is the focus of the current study, as identifying specific prognostic factors that can provide additional information on disease progression and treatment outcomes for patients with GS7 PCa would be of marked clinical benefit. GP4 is assigned to adenocarcinomas when they contain any of the following architectural patterns: Small/large fused glands, poorly formed glands, glomeruloid and cribriform architecture (4-6). The cribriform pattern is commonly associated with intraductal carcinoma (IDC), a distinct histopathological entity characterized by malignant cells spanning the lumen of prostate ducts and acini (7-9). Although specific morphologies of PCa, including cribriform architecture and IDC, have been recognized for decades, their independent clinical significance is only now emerging (8). Studies have demonstrated that IDC in biopsy and/or RP tissues is indicative Distinct DNA methylation alteration...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Distinct DNA methylation alterations are associated with cribriform architecture and intraductal carcinoma in Gleason pattern 4 prostate tumors

et al. 2017

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Strategies for discovery and validation of methylated and hydroxymethylated DNA biomarkers

2012

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DNA methylation, consisting of the addition of a methyl group at the fifth-position of cytosine in a CpG dinucleotide, is one of the most well-studied epigenetic mechanisms in mammals with important functions in normal and disease biology. Disease-specific aberrant DNA methylation is a well-recognized hallmark of many complex diseases. Accordingly, various studies have focused on characterizing unique DNA methylation marks associated with distinct stages of disease development as they may serve as useful biomarkers for diagnosis, prognosis, prediction of response to therapy, or disease monitoring. Recently, novel CpG dinucleotide modifications with potential regulatory roles such as 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine have been described. These potential epigenetic marks cannot be distinguished from 5-methylcytosine by many current strategies and may potentially compromise assessment and interpretation of methylation data. A large number of strategies have been described for the discovery and validation of DNA methylation-based biomarkers, each with its own advantages and limitations. These strategies can be classified into three main categories: restriction enzyme digestion, affinity-based analysis, and bisulfite modification. In general, candidate biomarkers are discovered using large-scale, genome-wide, methylation sequencing, and/or microarray-based profiling strategies. Following discovery, biomarker performance is validated in large independent cohorts using highly targeted locus-specific assays. There are still many challenges to the effective implementation of DNA methylation-based biomarkers. Emerging innovative methylation and hydroxymethylation detection strategies are focused on addressing these gaps in the field of epigenetics. The development of DNA methylation- and hydroxymethylation-based biomarkers is an exciting and rapidly evolving area of research that holds promise for potential applications in diverse clinical settings.

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Association of tissue promoter methylation levels of APC, TGFβ2, HOXD3 and RASSF1A with prostate cancer progression

Liu

Kron

Pethe

et al. 2011

Intl Journal of Cancer

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Aberrant promoter methylation is known to silence tumor-suppressor genes in prostate cancer (PCa). We correlated quantitative promoter methylation levels of APC, TGFb2 and RASSF1A in 219 radical prostatectomies diagnosed between 1998 and 2001 with clinicopathological follow-up data available including Gleason Pattern (GP), Gleason Score (GS) and pathological stage and explored their potential in predicting biochemical recurrence using univariate and multivariate analyses. We observed that the average methylation levels of APC increased significantly from GS 6 to GS7, and pT2 to pT3a, and that of TGFb2 increased from GS 6 to GS7, but not for RASSF1A. PCa samples were also stratified into high methylation (HM) and low methylation (LM) groups based on the PMR scores of all cases analyzed for each marker. The HM frequency of APC was greater in pT3a than pT2, and in GS 8 than GS 6. The HM frequency also increased significantly from GP3 to GP4 for APC, TGFb2 and RASSF1A. APC methylation level was a significant predictor of biochemical recurrence in univariate analysis (p-value 5 0.028). Finally, we combined methylation data of these three genes with the previously reported novel methylation biomarker HOXD3. Quantitative methylation assessment of a multiplex panel of markers, consisting of APC, HOXD3 and TGFb2, outperforms any single marker for the prediction of biochemical recurrence (p-value 5 0.017). Our study demonstrated that quantitative increase in promoter methylation levels of APC, HOXD3 and TGFb2 are associated with PCa progression.

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DNA methylation of HOXD3 as a marker of prostate cancer progression

Cited by 51 publications

References 46 publications

Distinct DNA methylation alterations are associated with cribriform architecture and intraductal carcinoma in Gleason pattern 4 prostate tumors

Distinct DNA methylation alterations are associated with cribriform architecture and intraductal carcinoma in Gleason pattern 4 prostate tumors

Strategies for discovery and validation of methylated and hydroxymethylated DNA biomarkers

Association of tissue promoter methylation levels of APC, TGFβ2, HOXD3 and RASSF1A with prostate cancer progression

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