What will be the consequences out of this?
Extract by Florent Mouliere / Montpellier and Nitzan Rosenfeld / Cambridge:
Circulating tumor DNA (ctDNA) is now widely investigated as a biomarker in translational and clinical research. However, despite the growing field of clinical applications, the biology of ctDNA remains unclear. In trying to learn about the origins of ctDNA, nature provides us with very few clues. One of the important accessible parameters is the size of those DNA fragments. In addition, a well-informed model of these sizes and biases can help design more efficient and accurate diagnostic methods. In PNAS, Jiang et al. take an important step in that direction.
Significance
We used massively parallel sequencing to study the size profiles of plasma DNA samples at single-base resolution and in a genome-wide manner. We used chromosome arm-level z-score analysis (CAZA) to identify tumor-derived plasma DNA for studying their specific size profiles. We showed that populations of aberrantly short and long DNA molecules existed in the plasma of patients with hepatocellular carcinoma. The short ones preferentially carried the tumor-associated copy number aberrations. We further showed that there were elevated amounts of mitochondrial DNA in the plasma of hepatocellular carcinoma patients. Such molecules were much shorter than the nuclear DNA in plasma. These findings have shed light on fundamental biological characteristics of plasma DNA and related diagnostic applications for cancer.
Abstract
The analysis of tumor-derived circulating cell-free DNA opens up new possibilities for performing liquid biopsies for the assessment of solid tumors. Although its clinical potential has been increasingly recognized, many aspects of the biological characteristics of tumor-derived cell-free DNA remain unclear. With respect to the size profile of such plasma DNA molecules, a number of studies reported the finding of increased integrity of tumor-derived plasma DNA, whereas others found evidence to suggest that plasma DNA molecules released by tumors might be shorter. Here, we performed a detailed analysis of the size profiles of plasma DNA in 90 patients with hepatocellular carcinoma, 67 with chronic hepatitis B, 36 with hepatitis B-associated cirrhosis, and 32 healthy controls. We used massively parallel sequencing to achieve plasma DNA size measurement at single-base resolution and in a genome-wide manner. Tumor-derived plasma DNA molecules were further identified with the use of chromosome arm-level z-score analysis (CAZA), which facilitated the studying of their specific size profiles. We showed that populations of aberrantly short and long DNA molecules existed in the plasma of patients with hepatocellular carcinoma. The short ones preferentially carried the tumor-associated copy number aberrations. We further showed that there were elevated amounts of plasma mitochondrial DNA in the plasma of hepatocellular carcinoma patients. Such molecules were much shorter than the nuclear DNA in plasma. These results have improved our understanding of the size profile of tumor-derived circulating cell-free DNA and might further enhance our ability to use plasma DNA as a molecular diagnostic tool.
Jiang P et al.: Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients. Proc Natl Acad Sci U S A. 2015 Feb 2. pii: 201500076.
http://www.pnas.org/content/early/2015/01/27/1500076112.abstract
http://www.pnas.org/content/early/2015/01/27/1500076112.abstract
microRNA 122 HAS BEEN IDENTIFIED WITH HEPATOCELLULAR CARCINOMA,WAS THEIR ANY EFFET ON SHORTENING THEZE LENGTHS OF TUMOR STRANDS ON THESE MICRO RNA ,why mitochondrial DNA were found smaller than the nuclear nes and how does it help in planning therapy.
well pointed out.
We also have this discussion at the web group of theTheodor-Billroth-Academy on LInkedin and Reinhold Kiehl, Hossein Rahmati Roudsari and Jan Voskuil made very important points and I try summarizing those:
-tumor markers as CEA or CA19-9 should be used for follow-up-never for making the diagnosis, as the overall accuracy is too small. Further tumor markers are expressed proteins on surface membranes and we learned from epithelial cysts that such can mimick a cancer, e.g.in spleen cysts very high CA-19-9 had been observed without any association of any cancer, nor during follow-up
Therefore, we by now do not know
- the influence and value and accuracy of detectable DNA
-when the best time is measuring it and how the values are influenced
-how storing would be best and how the interobserver variability might be
-when free DNA is measurable, how do such values differ after treatment
-are they proven being related to the observed cancer or assumed to be
-microRNA#s had been observed in ling cancer patients assuming having impact on spread and even cancer development but again: assumed!
-to my knowledge no standard protocol is accepted or suggested determining free DNA so far
Additionally Ijaz Jamall added a valuable insights deepening he comment from Hossein Rahmati Roudsari and Jan Voskuil (copy and pasted):
Ijaz Jamall: "I agree with Dr. Rousdari and Jan: one key factor to consider in measuring anything in the blood is its half-life and how to "normalize" the thing being measured - per ml blood or serum, per g protein, etc. because essentially we are measuring a concentration as opposed to a mass and dilution and binding kinetics or changes in hydration or albumin content can make huge a difference. In fact, diurnal variation can itself make a huge difference"
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