Diagnostic and Prognostic Epigenetic Biomarkers in Cancer

Costa-Pinheiro, Pedro; Montezuma, Diana; Henrique, Rui; Jerónimo, Carmen

doi:10.2217/epi.15.56

Cited by 193 publications

(139 citation statements)

References 120 publications

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“…Nonetheless, a combination of these three gene promoters significantly improved diagnostic performance when compared with previously published panels (Table 5). In our experience, the use of gene promoter panels, usually comprising two to four genes, improves sensitivity, without compromising specificity, as previously demonstrated for prostate and breast cancers, especially when tested in liquid biopsies [37,38]. Thus, the use of this gene panel might augment the performance of approved DNA methylation-based assays.…”

Section: Discussionsupporting

confidence: 54%

A novel DNA methylation panel accurately detects colorectal cancer independently of molecular pathway

et al. 2018

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Background: Colorectal cancer (CRC) is one of the most incident cancers, associated with significant morbidity and mortality, and usually classified into three main molecular pathways: chromosomal instability, microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). Currently, available screening methods are either costly or of limited specificity, impairing global implementation. More cost-effective strategies, including DNA methylation-based tests, might prove advantageous. Although some are already available, its performance is suboptimal, entailing the need for better candidate biomarkers. Herein, we tested whether combined use of APC, IGF2, MGMT, RASSF1A, and SEPT9 promoter methylation might accurately detect CRC irrespective of molecular subtype.Methods: Selected genes were validated using formalin-fixed paraffin-embedded tissues from 214 CRC and 50 non-malignant colorectal mucosae (CRN). Promoter methylation levels were assessed using real-time quantitative methylation-specific PCR. MSI and CIMP status were determined. Molecular data were correlated with standard clinicopathological features. Diagnostic and prognostic performances were evaluated by receiver operator characteristics curve and survival analyses, respectively.Results: Except for IGF2, promoter methylation levels were significantly higher in CRC compared to CRN. A threegene panel (MGMT, RASSF1A, SEPT9) identified malignancy with 96.6% sensitivity, 74.0% specificity and 91.5 positive predictive value (area under the curve: 0.97), independently of tumor location, stage, and molecular pathway. Conclusions:Combined promoter methylation analysis of MGMT/RASSF1A/SEPT9 displays a better performance than currently available epigenetic-based biomarkers for CRC, providing the basis for the development of a non-invasive assay to detect CRC irrespective of the molecular pathway.

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Section: Discussionsupporting

confidence: 54%

A novel DNA methylation panel accurately detects colorectal cancer independently of molecular pathway

et al. 2018

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“…This is the first study to show that hypermethylation of ST6GALNAC3 , ZNF660 , CCDC181 , and HAPLN3 can be detected in liquid biopsies from patients with PC. Methylated DNA has high potential as a biomarker, as it is frequently highly cancer‐specific, can be measured in, for example, tissue, blood, or urine, is easily detected with standard PCR‐based methods, and is relatively stable compared to RNA (Costa‐Pinheiro et al ., ). The presence of hypermethylated ctDNA was 100% cancer‐specific in our patient set for all four candidate genes investigated.…”

Section: Discussionmentioning

confidence: 97%

Biomarker potential of ST6GALNAC3 and ZNF660 promoter hypermethylation in prostate cancer tissue and liquid biopsies

et al. 2018

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Current diagnostic and prognostic tools for prostate cancer (PC) are suboptimal, leading to overdiagnosis and overtreatment. Aberrant promoter hypermethylation of specific genes has been suggested as novel candidate biomarkers for PC that may improve diagnosis and prognosis. We here analyzed ST6GALNAC3 and ZNF660 promoter methylation in prostate tissues, and ST6GALNAC3,ZNF660,CCDC181, and HAPLN3 promoter methylation in liquid biopsies. First, using four independent patient sample sets, including a total of 110 nonmalignant (NM) and 705 PC tissue samples, analyzed by methylation‐specific qPCR or methylation array, we found that hypermethylation of ST6GALNAC3 and ZNF660 was highly cancer‐specific with areas under the curve (AUC) of receiver operating characteristic (ROC) curve analysis of 0.917–0.995 and 0.846–0.903, respectively. Furthermore, ZNF660 hypermethylation was significantly associated with biochemical recurrence in two radical prostatectomy (RP) cohorts of 158 and 392 patients and remained significant also in the subsets of patients with Gleason score ≤7 (univariate Cox regression and log‐rank tests, P < 0.05), suggesting that ZNF660 methylation analysis can potentially help to stratify low‐/intermediate‐grade PCs into indolent vs. more aggressive subtypes. Notably, ZNF660 hypermethylation was also significantly associated with poor overall and PC‐specific survival in the RP cohort (n = 158) with long clinical follow‐up available. Moreover, as proof of principle, we successfully detected highly PC‐specific hypermethylated circulating tumor DNA (ctDNA) for ST6GALNAC3,ZNF660,HAPLN3, and CCDC181 in liquid biopsies (serum) from 27 patients with PC vs. 10 patients with BPH, using droplet digital methylation‐specific PCR analysis. Finally, we generated a three‐gene (ST6GALNAC3/CCDC181/HAPLN3) ctDNA hypermethylation model, which detected PC with 100% specificity and 67% sensitivity. In conclusion, we here for the first time demonstrate diagnostic biomarker potential of ST6GALNAC3 and ZNF660 methylation, as well as prognostic biomarker potential of ZNF660. Furthermore, we show that hypermethylation of four genes can be detected in ctDNA in liquid biopsies (serum) from patients with PC.

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“…The identification of genetic and epigenetic alterations in functional noncoding cis-regulatory elements also provides a source of biomarkers to monitor cancer development (187–190). For instance, genetic alterations mapping to the hTERT promoter are associated with advanced cancer staging and poor patient survival in glioma, bladder and thyroid cancer patients (40,45,191–193).…”

Section: Clinical Implications For the Functional Noncoding Genomementioning

confidence: 99%

Emergence of the Noncoding Cancer Genome: A Target of Genetic and Epigenetic Alterations

2016

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The emergence of whole-genome annotation approaches is paving the way for the comprehensive annotation of the human genome across diverse cell and tissue-types exposed to various environmental conditions. This has already unmasked the positions of thousands of functional cis-regulatory elements integral to transcriptional regulation, such as enhancers, promoters and anchors of chromatin interactions that populate the noncoding genome. Recent studies showed that cis-regulatory elements are commonly the targets of genetic and epigenetic alterations associated with aberrant gene expression in cancer. Here we review these findings to showcase the contribution of the noncoding genome and its alteration in the development and progression of cancer. We also highlight the opportunities to translate the biological characterization of genetic and epigenetic alterations in the noncoding cancer genome into novel approaches to treat or monitor disease.

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Diagnostic and Prognostic Epigenetic Biomarkers in Cancer

Cited by 193 publications

References 120 publications

A novel DNA methylation panel accurately detects colorectal cancer independently of molecular pathway

A novel DNA methylation panel accurately detects colorectal cancer independently of molecular pathway

Biomarker potential of ST6GALNAC3 and ZNF660 promoter hypermethylation in prostate cancer tissue and liquid biopsies

Emergence of the Noncoding Cancer Genome: A Target of Genetic and Epigenetic Alterations

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