Do we use the appropriate controls for the identification of informative methylation markers for early cancer detection?

It is possible to miss potential DNA methylation markers of tumorigenesis because profiling results are initially filtered on the basis of inappropriate controls

Noninvasive approaches to detect methylation-based markers to monitor gliomas

In this review, we summarize the current approaches used to detect glioma tissue-derived DNA methylation markers in liquid biopsy specimens with the aim to diagnose, prognosticate and potentially track treatment response and evolution of patients with gliomas

Genome-scale screen for DNA methylation-based detection markers for ovarian cancer.

The identification of sensitive biomarkers for the detection of ovarian cancer is of high clinical relevance for early detection and/or monitoring of disease recurrence. We developed a systematic multi-step biomarker discovery and verification strategy to identify candidate DNA methylation markers for the blood-based detection of ovarian cancer

Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study

Epigenetic alterations measured in blood may help guide breast cancer treatment. The multisite prospective study TBCRC 005 was conducted to examine the ability of a novel panel of cell-free DNA methylation markers to predict survival outcomes in metastatic breast cancer (MBC) using a new quantitative multiplex assay (cMethDNA)

DNA methylation markers in the detection of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and has a poor prognosis. Epigenetic modification has been shown to be deregulated during HCC development by dramatically impacting the differentiation, proliferation, and function of cells. One important epigenetic modification is DNA methylation during which methyl groups are added to cytosines without changing the DNA sequence itself. Studies found that methylated DNA markers can be specific for detection of HCC. On the basis of these findings, the utility of methylated DNA markers as novel biomarkers for early-stage HCC has been measured in blood, and indeed superior sensitivity and specificity have been found in several studies when compared to current surveillance methods. However, a variety of factors currently limit the immediate application of these exciting biomarkers. In this review, we provide a detailed rationalisation of the approach and basis for the use of methylation biomarkers for HCC detection and summarise recent studies on methylated DNA markers in HCC focusing on the importance of the aetiological cause of liver disease in the mechanisms leading to cancer.</p

Genome-wide methylome analysis using MethylCap-seq uncovers 4 hypermethylated markers with high sensitivity for both adeno- and squamous-cell cervical carcinoma

Background: Cytology-based screening methods for cervical adenocarcinoma (ADC) and to a lesser extent squamous-cell carcinoma (SCC) suffer from low sensitivity. DNA hypermethylation analysis in cervical scrapings may improve detection of SCC, but few methylation markers have been described for ADC. We aimed to identify novel methylation markers for the early detection of both ADC and SCC. Results: Genome-wide methylation profiling for 20 normal cervices, 6 ADC and 6 SCC using MethylCap-seq yielded 53 candidate regions hypermethylated in both ADC and SCC. Verification and independent validation of the 15 most significant regions revealed 5 markers with differential methylation between 17 normals and 13 cancers. Quantitative methylation-specific PCR on cervical cancer scrapings resulted in detection rates ranging between 80% and 92% while between 94% and 99% of control scrapings tested negative. Four markers (SLC6A5, SOX1, SOX14 and TBX20) detected ADC and SCC with similar sensitivity. In scrapings from women referred with an abnormal smear (n = 229), CIN3+ sensitivity was between 36% and 71%, while between 71% and 93% of adenocarcinoma in situ (AdCIS) were detected; and CIN0/1 specificity was between 88% and 98%. Compared to hrHPV, the combination SOX1/SOX14 showed a similar CIN3+ sensitivity (80% vs. 75%, respectively, P>0.2), while specificity improved (42% vs. 84%, respectively, P < 10(-5)). Conclusion: SOX1 and SOX14 are methylation biomarkers applicable for screening of all cervical cancer types

Epigenetic Biomarkers for Environmental Exposures and Personalized Breast Cancer Prevention.

Environmental and lifestyle factors are believed to account for &gt;80% of breast cancers; however, it is not well understood how and when these factors affect risk and which exposed individuals will actually develop the disease. While alcohol consumption, obesity, and hormone therapy are some known risk factors for breast cancer, other exposures associated with breast cancer risk have not yet been identified or well characterized. In this paper, it is proposed that the identification of blood epigenetic markers for personal, in utero, and ancestral environmental exposures can help researchers better understand known and potential relationships between exposures and breast cancer risk and may enable personalized prevention strategies

Unraveling the Role of Epigenetics in Aging and Chronic Disease.

Healthy aging is defined as aging in the absence of chronic diseases that limit physical function and mobility. With the increasingly high prevalence of chronic diseases and their risk factors in the United States, it is important to better understand the contributors and predictors of health and longevity. Molecular markers of the epigenome provide one novel set of biomarkers to investigate the intersection of the effects of genetic variation and environmental variation in the initiation and progression of chronic disease. This dissertation focuses on (1) investigating associations between 26,428 DNA methylation markers and chronological age, (2) elucidating the environmental and genetic components of the variation of 26,428 DNA methylation markers, and, finally, (3) predicting aging with DNA methylation markers sites in an African-American population of sibships from the Jackson, MS field center of the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We found that 27% of the genome-wide DNA methylation sites are significantly associated with age. The majority of DNA methylation sites (88%) have significant heritabilities, and there is evidence of an age-related genetic component to this heritability. Finally, when predicting aging, inflammatory biomarkers and DNA methylation markers, together, were found to explain 14% of the variation in aging. This dissertation illustrates that DNA methylation patterns measured in epidemiological studies may be able to provide new insights into the molecular processes underlying aging and chronic disease development.PHDEpidemiological ScienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/99896/1/alaz_1.pd

Hypermethylation of DNA Methylation Markers in Non-Cirrhotic Hepatocellular Carcinoma

Aberrant DNA methylation changes have been reported to be associated with carcinogenesis in cirrhotic HCC, but DNA methylation patterns for these non-cirrhotic HCC cases were not examined. Therefore, we sought to investigate DNA methylation changes on non-cirrhotic HCC using reported promising DNA methylation markers (DMMs), including HOXA1, CLEC11A, AK055957, and TSPYL5, on 146 liver tissues using quantitative methylation-specific PCR and methylated DNA sequencing. We observed a high frequency of aberrant methylation changes in the four DMMs through both techniques in non-cirrhotic HCC compared to cirrhosis, hepatitis, and benign lesions (p &lt; 0.05), suggesting that hypermethylation of these DMMs is specific to non-cirrhotic HCC development. Also, the combination of the four DMMs exhibited 78% sensitivity at 80% specificity with an AUC of 0.85 in discriminating non-cirrhotic HCC from hepatitis and benign lesions. In addition, HOXA1 showed a higher aberrant methylation percentage in non-cirrhotic HCC compared to cirrhotic HCC (43.3% versus 13.3%, p = 0.039), which was confirmed using multivariate linear regression (p &lt; 0.05). In summary, we identified aberrant hypermethylation changes in HOXA1, CLEC11A, AK055957, and TSPYL5 in non-cirrhotic HCC tissues compared to cirrhosis, hepatitis, and benign lesions, providing information that could be used as potentially detectable biomarkers for these unusual HCC cases in clinical practice.</p