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Comparative Study
. 2009 Feb;100(2):303-9.
doi: 10.1111/j.1349-7006.2008.01021.x.

Quantification of circulating cell-free DNA in the plasma of cancer patients during radiation therapy

Chao Cheng  1 , Motoko Omura-Minamisawa, Yun Kang, Takamitsu Hara, Izumi Koike, Tomio Inoue
Affiliations
Comparative Study

Quantification of circulating cell-free DNA in the plasma of cancer patients during radiation therapy

Chao Cheng et al. Cancer Sci. 2009 Feb.

Abstract

Cell-free plasma DNA is elevated in cancer patients and decreases in response to effective treatments. Consequently, these nucleic acids have potential as new tumor markers. In our current study, we investigated whether the plasma DNA concentrations in patients with cancer are altered during the course of radiation therapy. To first determine the origin of cell-free plasma DNA, plasma samples from mice bearing transplanted human tumors were analyzed for human-specific and mouse-specific cell-free DNA. Human-specific DNA was detectable only in plasma from tumor-bearing mice. However, mouse-specific plasma DNA was significantly higher in tumor-bearing mice than in normal mice, suggesting that cell-free plasma DNA originated from both tumor and normal cells. We measured the total cell-free plasma DNA levels by quantitative polymerase chain reaction in 15 cancer patients undergoing radiation therapy and compared these values with healthy control subjects. The cancer patients showed higher pretreatment plasma DNA concentrations than the healthy controls. Eleven of these patients showed a transient increase of up to eightfold in their cell-free plasma DNA concentrations during the first or second week of radiation therapy, followed by decreasing concentrations toward the end of treatment. In two other cancer patients, the cell-free plasma DNA concentrations only decreased over the course of the treatment. The total cell-free plasma DNA levels in cancer patients thus show dynamic changes associated with the progression of radiation therapy. Additional prospective studies will be required to elucidate the potential clinical utility and biological implications of dynamic changes in cell-free plasma DNA during radiation therapy.

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Figures

Figure 1
Figure 1
Concentrations of (a) human‐specific DNA and (b) mouse‐specific DNA in the plasma of mice bearing various types of human tumors (formula image, SROV‐3; formula image, DLD‐1; formula image, SQ5‐SLK; formula image, KM12C; formula image, A431; formula image, RPMI 1788) and in control mice. (a) Sixteen of 24 plasma samples from mice bearing human tumors, but none of the 11 samples from control mice, contained human‐specific genomic DNA (P < 0.001). The concentration of human‐specific DNA in plasma varied according to the implanted tumor cell type. (b) Samples from mice bearing human tumors (n = 24) contained significantly greater concentrations of cell‐free mouse DNA than samples from control mice (n = 11) (P < 0.01). When the concentration of mouse‐specific DNA of each tumor type were compared with the control group, the difference depended on the tumor type implanted.
Figure 2
Figure 2
The concentrations of cell‐free (a) 100‐bp genomic DNA, (b) 400‐bp genomic DNA, (c) mitochondrial DNA, and (d) the relative expression of β‐actin mRNA in plasma samples from cancer patients (n = 15) and healthy controls (n = 20). An mRNA sample from patient 15 was not available. Control plasma samples for the measurement of 400‐bp genomic DNA and mRNA were not available from all 20 healthy subjects (n = 12, and n = 19, respectively). cDNA reverse‐transcribed from 2 µg mRNA from exponentially growing HeLa cells was used as a standard. All types of DNA except for mitochondrial DNA were significantly elevated in plasma samples from cancer patients compared with healthy controls. (a) 100 bp genomic DNA, P < 0.05; (b) 400‐bp genomic DNA, P < 0.01; (c) mitochondrial DNA, P = 0.083. (d) mRNA expression levels were higher in cancer patients than in healthy controls (P < 0.05). (e) DNA integrity (the ratio of 400‐bp fragments/100‐bp fragments) was higher in samples from cancer patients than in healthy controls (P < 0.01).
Figure 3
Figure 3
Dynamic changes with time in the plasma concentrations of (a) 100‐bp and 400‐bp genomic DNA and (b) mitochondrial DNA in samples from cancer patients undergoing radiation therapy. Plasma samples were obtained before radiation therapy (day 0), on the third day of treatment, and then every 1 or 2 weeks during the treatment period. Initial plasma concentrations prior to treatment were normalized to 100% and the data are reported in relation to this initial value. (a) Top panels, 100‐bp DNA; bottom panels, 400‐bp DNA. (b) Mitochondrial DNA.
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