The origin of blood-derived epigenetic cancer markers

Written by Dr Ivana Samarzija, University of Zagreb, Croatia

Epigenetic processes have been unequivocally linked to cancer and other complex diseases. DNA methylation, a major epigenetic mechanism, is perturbed in cancer tissue in the way that global hypomethylation appears at the same time as hypermethylation at gene promoters. In addition to epigenetic studies on tumor tissue, in the last decade, there have been several reports showing correlation between peripheral blood DNA methylation and tumor status. Given the fact that peripheral blood is easily accessible, it is clear that its DNA methylation analysis holds a promise in finding suitable cancer markers.

Attributed to: Crystal (Crystl) from Bloomington, USA, Wikimedia Commons
Attributed to: Crystal (Crystl) from Bloomington, USA, Wikimedia Commons

Two sources of epigenetic alterations can be detected in patients blood as a consequence of tumor development. Firstly, the amount of so called cell-free circulating DNA was shown to be elevated in some cases of malignancy. It was shown that in some cases, this DNA has genetic and epigenetic marks of a tumor tissue, therefore it is of a tumor origin. The main source of this DNA is cell death either by apoptosis or necrosis. Circulating cell-free DNA’s most obvious applications are in cancer detection and monitoring. However, the main subject of this blog is the origin of changes in peripheral blood cell DNA methylation as a consequence of cancer development.

Recent studies have suggested that DNA methylation markers from peripheral blood cells might serve as diagnostic, early detection/risk or prognostic cancer markers. Several publications exist (example ref. 1) that show such correlation in different cancer types: bladder, lung, ovarian, breast , pancreatic, colorectal adenoma, head and neck squamous cell carcinoma, gastric adenocarcinoma, etc. Those studies interrogated either global methylation, promoters of single genes or genome-wide methylation patterns that are related to cancer.

Several scenarios exist that can explain alterations in DNA methylation in peripheral blood cells in cancer cases. In a first such scenario, so called constitutional epimutation takes place in all tissues of a body, including blood,  and predisposes individual towards cancer or other disease. The first publication showing constitutional epimutation in humans was that by Gazzoli et al. (ref. 2) showing abberant methylation of the MLH1 mismatch repair gene detected in peripheral blood which predisposes to the development of cancer. If this scenario is on play it might be possible that epigenetic changes predict risk of a cancer a way ahead before it is detectable by common methods.

The second possibility is that the presence of cancer influences methylation in blood cells. It is a well known fact that tumor does not develop as an isolated phenomenon, but rather influences other organs, including the immune system. Nevertheless, it is not clear how it can affect peripheral blood DNA methylation. Tumor tissue might use nutrients involved in methyl-group metabolism, or interference with hematopoiesis might take place, especially through inflammation that is characteristic of cancer tissue.

The third possibility is that altered DNA methylation is a consequence of environmental effects that are also targeting cancer tissue of origin. The unique characteristics of epigenetic marks in comparison to their genetic counterparts is their plasticity in response to enviromental influences. Factors that are present in enviroment (carcinogens and pollutants) or intrinsic factors that can be modulated by the environment (like estrogens) leave an imprint in the DNA of cells that are unrelated to the target organ and indicate the predisposition to develop a cancer.

In any case, studying peripheral blood DNA methylation can be informative in the sense of predicting or identifying tumorigenesis mechanisms.

It needs to be mentioned that studies also exist that failed to find correlation between peripheral blood DNA methylation and cancer status. However, like it was suggested by some researchers, the association between peripheral blood DNA methylation and cancer appearance might be different depending on experimental methods used and the region of DNA targeted for measuring global/local methylation levels.


  1. Moore LE, Pfeiffer RM, Poscablo C, Real FX, Kogevinas M, Silverman D, García-Closas R, Chanock S, Tardón A, Serra C, Carrato A, Dosemeci M, García-Closas M, Esteller M, Fraga M, Rothman N, Malats N. Genomic DNA hypomethylation as a biomarker for bladder cancer susceptibility in the Spanish Bladder Cancer Study: a case-control study. Lancet Oncol. 2008 Apr;9(4):359-66
  2. Gazzoli I, Loda M, Garber J, Syngal S, Kolodner RD. A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor. Cancer Res. 2002 Jul 15;62(14):3925-8.

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