Figure 1: Is Cell-Free DNA our next hope to cancer detection?
Do you know that our marine environment is succumbing into severe pollution from corroding shipwrecks? With water making up to 71% of the earth surface, looking for shipwrecks that had sunk into deep waters is synonymous to searching for a needle in a haystack.
Does that actually resemble a kind of disease in our body too? Yes, that is what I am talking about; Cancer and Tumors. While all tumors are not necessarily cancerous, malignant tumors are essentially cancer. Regardless of tumors being benign or malignant, they are basically tissues that are composed of cells whose DNA are mutated, rendering them the abnormal capability to proliferate exponentially without regulation. These usually result in abnormal lesions or swelling of an organ, increasing the competition for “nutrients” with the healthy normal cells, thereby posing potential health hazards to the host. Similarly, removal of these tumor cells will halt the deteriorating health impacts and allow the host to regain its health. Unfortunately, searching for these tumors is not as simple as it seems to be.
Needle-tissue biopsy is traditionally the gold standard for cancer diagnosis. However, this is a highly invasive expensive medical procedure that involves puncturing a needle into the body to obtain tissue samples for more in-depth examination of the cells. Hence, scientists have been diligently researching for the past 2 decades for alternatives that could by-pass needle-tissue biopsy and make cancer diagnosis more efficient and less invasive.
Taking a step back, if floating debris from shipwrecks could lead to the exact location of its host, is there something similar that can aid the physicians to detect the presence of tumors?
Figure 3: Can scientists uncover the mystery of these floating cell free DNA in relevance to Tumors?
Yes, that floating debris in relation with tumors is Cell-Free DNA. In fact, cell-free DNA is not a novel finding. Its existence was first discovered back in 1948 by Mandel and Matis, although debates on the clinical application of cell-free DNA in tumor diagnosis only began in1977.
As the name implies, “cell-free DNA” refers to DNA compounds not found in a cell. Traditionally, DNA is usually localized in protecting organelles such as nucleus and mitochondria. The exciting breakthrough begins when serum DNA levels are significantly elevated in cancer patients compared to healthy individuals, especially in patients with metastatic Tumors. In normal individuals, concentration of cell-free DNA varies from 0 – 100ng/ml of blood.
However, this extravagant surge in cell-free DNA concentration is not limited to cancer patients. Patients languishing in clinical conditions such as rheumatoid disease, trauma, myocardial infarction, fever and inflammatory diseases have similar phenomenon. Although their presence has been well documented in various clinical conditions, the origin and their liberation mechanism remains poorly understood.
Figure 4: Scientists believe that DNA is usually stored safely in the nucleus of cells.
Since there is so much interest and promising results from the available studies, does that mean, cell free DNA is seeing the light at the end of the tunnel?
Unfortunately, studies regarding the application of cell-free DNA in routine clinical diagnostics are only at its budding stage. In order to succeed, there are some major details to be ironed out. The foremost limitation is that the majority of the research was done with small sample size (n < 100). For clinical application, there is a need to have a huge sample size to smooth out details such as gender differences, racial/national diversities and age group differences. Hence the conclusion derived from the basis of the power of statistical tests used in these studies remain questionable.
Second challenge is the establishment of reference intervals for the healthy population. This aspect requires an immense amount of resources such as extensive monitoring, documentation and meticulous consideration to all variable attributes from pre-analytical to analytical process.
Third issue is the variation observed in the various protocols and assays. Different studies have used different sample collecting tubes, different DNA isolation, quantitation and detection methods, while downstream processing procedures such as centrifugation speed have not been standardized as well too.
Therefore, although cell-free DNA is an exciting breakthrough in the field of clinical diagnostics for early cancer detection and monitoring, there are huge complicated gaps yet to fill. Only when the above limitations are overcome, the “shipwreck – tumors/cancer” will remain secluded, while scientists will continue to “dive” deeper to look for the elusive “debris – cell free DNA”.
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