Cell-Free DNA Source of Cell-Free DNA DNA in Urine Other Cancer Indicators Indicator Limitations

Cell-Free DNA

The presence of circulating cell-free DNA has been documented as early as the 1940's (Mandel and Metais, 1947), however it was not until the 1970's that a correlation between elevated levels of circulating DNA and several human disorders, including cancer (Koffler et al., 1973; Leon et al., 1977; Steinman, 1975), was established. Using a radio-immunoassay, Leon et al., 1977 reported that levels of DNA in serum were greatly elevated in patients with various types of cancer (180 ± 38 ng/mL) compared with healthy controls (13 ± 3 ng/mL). Patients with metastatic diseases were found to have DNA levels approximately twice as high as non-metastatic patients - 209 ± 39 ng/mL and 100 ± 30 ng/mL, respectively (Leon et al. 1977). Shapiro et al. (1983) measured serum DNA in patients with either malignant or benign disease of the gastrointestinal tract, and found concentrations of 412 ± 63 ng/mL and 118 ± 14 ng/mL, respectively. More recently, Chang et al. (2002), Wu et al (2002), and Taback et al. (2004) showed that elevated levels of circulating DNA can be identified consistently in patients with neoplastic diseases compared with healthy controls. Below is a brief summary of the cancer types that are positively correlated with elevated levels of circulating DNA.

Authors (year)	Cancer Type	Results
Silva et al. (1999)	Breast	Plasma DNA in breast cancer patients ranged from 24-170 ng/mL; in healthy controls DNA levels ranged from 0-45 ng/mL
Flamini et al. (2006)	Colorectal	Median DNA concentration was about 5-fold higher in colorectal cancer patients than in healthy donors.
Shapiro et al. (1983)	Gastrointestinal (pancreatic, gastric)	Patients with benign GI disease had mean DNA levels of 118 ± 14 ng/mL, whereas patients with malignant GI disease had 412 ± 63 ng/mL.
Ren et al. (2006)	Hepatocellular	Compared with the healthy volunteers, a significantly higher circulating plasma DNA level was found in the patients with hepatocellular carcinoma (mean 47.1±43.7 ng/ml), or liver cirrhosis (mean 30.0±13.3 ng/ml).
Sozzi et al. (2003)	Lung	Median concentration of circulating plasma DNA in lung cancer patients was almost eight times the value detected in age-, sex-, and smoking-matched controls (24.3 vs 3.1 ng/mL)
Sozzi et al.(2001)	Lung	In patients, the mean plasma DNA concentration just prior to surgery was 318 ng/mL (controls = 18 ng/mL). In clinically relapse-free individuals, DNA concentrations in the follow-up plasma sample (34 ng/ml on average) were significantly lower than at the time of surgery and comparable with the value observed in the control group.
Maebo (1990)	Lung	Mean plasma DNA level was significantly higher in the patients with lung cancer than that in the patients with benign pulmonary diseases or in healthy controls. In lung cancer patients who responded to treatment, the plasma DNA levels were significantly decreased after treatment, while its levels were elevated in the patients whose treatment was unsuccessful.
Taback et al. (2004)	Melanoma	Serum DNA in healthy donors ranged from 9-79 ng/mL, while patients with metastatic melanoma had serum DNA concentrations of 411-2 821 ng/mL.
Wu et al. (2002)	Non-Hodgkin lymphoma, Leukemia, Multiple myeloma, Lung, Bladder, Hepatoma, Cervic, Gastric, Esophageal,	Healthy volunteers were found to have serum DNA concentrations of 57.1 ± 30.6 ng/mL, while the serum cell-free DNA was elevated in almost all types of malignant diseases.
Giacona et al. (1998)	Pancreatic Colorectal	90% of pancreatic carcinoma patients had serum DNA levels >100 ng/mL. Only 40% of colorectal carcinoma patients had DNA levels in similar concentrations.
Papadopoulou et al. (2004)	Prostate	Free circulating DNA can be detected in patients with prostate cancer compared with disease-free individuals.
Jung et al. (2004)	Prostate	Patients with localized cancer had DNA plasma within the reference interval. Increased plasma DNA was found in patients with lymph node and distant metastases.
Allen et al. (2004)	Prostate	Patients with benign prostatic hypertrophy (BPH) has significantly lower DNA levels than patients with either high-gradeprostatic intraepithelial neoplasia (PIN) or adenocarcinoma.
Boddy et al. (2005)	Prostate	Patients with prostate cancer had significantly higher level of DNA than those in a low-risk benign group as well as healthy controls The low-risk benign group has significantly higher DNA levels than the healthy control group.

Table 1. A summary of the cancer types reported in literature correlated with elevated levels of circulating DNA

Allen D, Butt A, Cahill D, Wheeler M, Popert R, Swaminathan R. Role of cell-free plasma DNA as a diagnostic marker for prostate cancer. Ann N Y Acad Sci 2004; 1022: 76-80.

Boddy JL, Gal S, Malone PR, Harris AL, Wainscoat JS. Prospective study of quantitation of plasma DNA levels in the diagnosis of malignant versus benign prostate disease. Clin Cancer Res 2005; 11: 1394-1399.

Chang HW, Lee SM, Goodman SN, Singer G, Cho SKR, Sokoll LJ, et al. Assessment of plasma DNA levels, allelic imbalance, and CA 125 as diagnostic tests for cancer. J Natl Cancer Inst 2002; 94: 1697-1703.

Flamini E, Mercatali L, Nanni O, Calistri D, Nunziatini R, Zoli W, et al. Free DNA and carcinoembryonic antigen serum levels : An important combination for diagnosis of colorectal cancer. Clin Cancer Res 2006; 12: 6985-6988.

Giacona MB, Ruben GC, Iczkowski KA, Roos TB, Porter DM, Sorenson GD. Cell-free DNA in human blood plasma: Length measurements in patients with pancreatic cancer and healthy controls. Pancreas 1998; 17: 89-97.

Jung K, Stephan C, Lewandowski M, Klotzek S, Jung M, Kristiansen G, et al. Increased cell-free DNA in plasma of patients with metastatic spread in prostate cancer. Cancer Lett 2004; 205: 173-180.

Koffler D, Agnello V, Winchester R, Kunkel HG. The occurrence of single-stranded DNA in the serum of patients with systemic lupus erythematosus and other diseases. J Clin Invest 1973; 52: 198-204.

Leon SA, Ehrlich GE, Shapiro B, Labbate VA. Free DNA in the serum of rheumatoid arthritis patients. J Rheumatol 1977; 4: 139-143.

Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res 1977; 37: 646-650.

Maebo A. Plasma DNA level as a tumor marker in primary lung cancer. Nihon Kyobu Shikkan Gakkai Zasshi 1990; 28: 1085-1091.

Mandel P, Metais P. Les acides nucléiques du plasma sanguin chez l'homme. Acad Sci Paris 1948; 142: 241-243.

Papadopoulou E, Davilas E, Sotiriou V, Koliopanos A, Aggelakis F, Dardoufas K, et al. Cell-free DNA and RNA in plasma as a new molecular marker for prostate cancer. Oncol Res 2004; 14: 439-445.

Ren N, Qin LX; Tu H, Liu YK, Zhang BH, Tang ZY. The prognostic value of circulating plasma DNA level and its allelic imbalance on chromosome 8p in patients with hepatocellular carcinoma. J Cancer Res Clin Oncol 2006; 132: 399-407.

Shapiro B, Chakrabarty M, Cohn EM, Leon SA. Determination of circulating DNA levels in patients with benign or malignant gastrointestinal disease. Cancer 1983; 51: 2116-2120.

Silva JM, Dominguez G, Garcia JM, Gonzalez R, Villanueva MJ, Navarro F, et al. Presence of tumor DNA in plasma of breast cancer patients: Clinicopathological correlations. Cancer Res 1999; 59: 3251-3256.

Sozzi G, Conte D, Leon M, Ciricione R, Roz L, Ratcliffe C, et al. Quantification of free circulating DNA as a diagnostic marker in lung cancer. J Clin Oncol 2003; 21: 3902-3908.

Sozzi G, Conte D, Mariani L, Lo Vullo S, Roz L, Lombardo C, et al. Analysis of circulating tumor DNA in plasma at diagnosis and during follow-up of lung cancer patients. Cancer Res 2001; 61: 4675-4678.

Steinman CR. Free DNA in serum and plasma from normal adults. J Clin Invest 1975; 56: 512-515.

Taback B, O'Day SJ, Hoon DS. Quantification of circulating DNA in the plasma and serum of cancer patients. Ann N Y Acad Sci 2004; 1022: 17-24.

Wu TL, Zhang D, Chia JH, Tsao KH, Sun CF, Wu JT. Cell-free DNA: measurement in various carcinomas and establishment of normal reference range. Clin Chim Acta 2002; 321: 77-87.

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