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Why was the gold standard whole-genome bisulfite sequencing not used?
They did attempt using WGBS, however this approach was high cost and inefficient for circulating cell-free DNA as DNA degraded during bisulfite conversion leading to limited information recovered for CpGs.

What was the point of comparing the cfMedDip seq to the hybrid-capture mutation sequencing?
cfMeDIP–seq was efficient between observed and expected numbers for  differentially methylated regions with low percentage of  false discovery rate, while hybrid capture mutation sequencing, detected mutations inefficiently. This highlights the excellent  sensitivity of cfMeDIP–seq for the detection of cancer-derived DNA. Furthermore, cfMeDIP–seq can enrich CpG-rich, enhancing cost-effectiveness and more information would be recovered by increasing initial DNA input.

How comparable are the two different methylome sequencing technologies  MeDip-seq and RRBS?

MeDip-seq is genome purification technique to enrich methylated DNA sequences, using 5-methylcytosine antibody. Whereas, RRBS uses restriction enzymes digestion and enrich high CpG regions using bisulfite sequencing.

Why is the bisulfite-free approach a benefit when investigating tumour methylomes?

They were able to find hypermethylated regions in tumour tissue through circulating tumor DNA which could be a  non-invasive characterization of active transcription-factor networks in cancer using cfMeDIP–seq. Investigating tumour methylomes enables tumour classification and distinguishes patients with early-stage of pancreatic cancer from healthy controls using plasma cfDNA.

Thank you,
Nayra Al-Thani

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Epigenetic changes represent potential molecular elements which control relevant physiological and pathological features, thereby contributing to the natural history of human disease. These epigenetic biomarkers can incorporate information regarding the effects of the environment and lifestyle on health and disease, and monitor the effect of applied therapies. Technologies used to analyze biomarkers are constantly improving, becoming much easier to use.

In the coming years, epigenetics will generate new diagnostics and therapy strategies. Therefore, it is noteworthy that both clinical laboratory technicians and clinical practitioners will be required to increase their knowledge on new epigenetic technologies and platforms. The future epigenetics will give us the direction of modern medicine toward a more personalized and precise practice. Precision medicine aims to improve, via theragnosis and predicting and monitoring treatments, the safety and efficacy of medical treatments in order to save on healthcare costs. For example, in a cancer research, a number of biomarkers have been announced already in USA and in European countries to revolutionize healthcare systems.

EpiCell Diagnostics offers in vitro diagnostics ( IVDs) certified direct-to-consumer biomarker tests. We also collaborate with research institutions, aiming to assist them with the current market analysis and to volunteer studies participants for all stages of methylation-based IVD products approval.

European and US approved IVDs that are marketed directly to consumers without the involvement of a health care provider are called direct-to-consumer tests (DTC). These tests generally request the consumer collect a specimen, such as fresh blood or blood plasma (only via physicians, paramedics, or diagnostic labs), saliva or urine, and send it to the company for testing and analysis.

Direct-to-consumer testing is expanding the number of people who are able to get epigenetic testing of their DNA. These diagnostics test kits have enabled vast research and industry into patterns of DNA methylation that differ between normal and diseased states and have yielded an abundance of peer-reviewed, scientific studies called epigenome-wide association studies (EWAS).

The tests have varying levels of evidence that support their claims. Some direct-to-consumer tests have a lot of scientific and clinical data to support the information they are providing, while other tests do not have as much supporting data. There can be agreements in the clinical community about the role that different epigenetic variants have in contributing to disease, and new information is being learned every day. However, not all variants that contribute to a person's risk of getting a disease or condition may be known, so it is important that consumers understand, that a negative test result means they still may be at risk for a particular disease or condition. Therefore, annual check-ups and epigenetic screenings may be useful, particularly for consumers who allocated into different risk groups.

The US and EU Regulators define IVDs, including epigenetic direct-to consumer tests, as medical devices. The specific regulatory requirements depend on the risk classification, sensitivity, and specificity of the individual IVD.

The diagnostic sensitivity is a probability of the test to give a positive result in the presence of targeted marker, while diagnostic specificity is a probability of the test to give a negative result in the absence of the targeted marker, as defined in Commission Decision of 27 November 2009 (nr 2009/886/EC).

Follow the directions provided with the test. If you do not follow the directions carefully there is a chance the test may not work correctly.

Talk with your patient about which tests might provide useful information about his health. Make sure you understand the benefits as well as the limitations of any test before use. We at EpiCell Diagnostics will provide you with all necessary information regarding efficacy, specificity, and sensitivity of available diagnostics tests.

For epigenetic tests, you may also consider speaking with a clinical biologist, pharmacist, medical affairs industry member, board-certified medical geneticist, or other equivalent healthcare provider. Do not hesitate to contact us to receive further information about epigenetic services as well.

Some epigenetic test results do not report all known epigenetic variants that might contribute to an increased risk of disease. A positive result should also not be used alone to make decisions about treating a disease.

Remember that epigenetic tests are not a substitute for a traditional health care evaluation, including health screenings and medical history.

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Epigenetic changes represent potential molecular elements which control relevant physiological and pathological features, thereby contributing to the natural history of human disease. These epigenetic biomarkers can incorporate information regarding the effects of the environment and lifestyle on health and disease, and monitor the effect of applied therapies.

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New paper on classifying Sarcomas with DNA methylation profiling

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New paper on classifying Sarcomas with DNA methylation profiling

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national center for biotechnology information

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Sarcoma classification by DNA methylation profiling - PubMed

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Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer vari ...

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I have chosen this paper on classifying tumour types bases on cell-free DNA methylomes - I must admit I was hoping to select a more recent applied paper but on reading a few I thought the inferences were a little weak.

This is a Nature paper so quite heavy going and there are a lot of new methods and statistical techniques and simulations but the take-home message is that there appear to be distinct tumour-specific  DNA methylomes that can be detected in cell-free circulating DNA. The next challenge is to develop sensitive and specific assays before we can see this type of biomarker routinely used in the clinic.

A few pointers to think about when reading the paper:

Why was the gold standard whole-genome bisulfite sequencing not used?

What was the point of comparing the cfMedDip seq to the hybrid-capture mutation sequencing?
How comparable are the two different methylome sequencing technologies MeDip-seq and RRBS?
Why is the bisulfite-free approach a benefit when investigating tumour methylomes?