Plasma Circulating Cell-free DNA Integrity as a Promising Biomarker for Diagnosis and Surveillance in Patients with Hepatocellular Carcinoma

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Abstract

The clinical significance of circulating cell-free DNA (cfDNA) integrity as diagnostic and surveillance biomarker in hepatocellular carcinoma (HCC) was investigated and compared to that of alpha fetoprotein (AFP). Liver cancer patients had lower cfDNA integrity than those with benign diseases ( P = 0.0167) and healthy individuals ( P = 0.0025). Patients with HCC and non-HCC liver cancers ( P = 0.7356), and patients with benign diseases and healthy individuals ( P = 0.9138) had comparable cfDNA integrity respectively. cfDNA integrity increased after hepatectomy in cancer patients ( P = 0.0003). The AUCs for detecting HCC by cfDNA integrity and AFP were 0.705 ( P = 0.005) and 0.605 ( P = 0.156), respectively. We found cfDNA integrity decreased in HCC patients and has the potential as promising biomarker for HCC diagnosis and treatment surveillance.

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Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients.

Peiyong Jiang, Carol Chan, K. C. Allen Chan … (2015)

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.

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Prediction of breast tumor progression by integrity of free circulating DNA in serum.

Suzanne Hiramatsu, Silvana Martino, Armando E. Giuliano … (2006)

Cell-free DNA circulating in serum is a candidate molecular biomarker for malignant tumors. Unlike uniformly truncated DNA released from apoptotic cells, DNA released from dead cancer cells varies in size. Serum DNA integrity, the ratio of longer fragments to total DNA, may be clinically useful for detecting breast cancer progression. Serum samples from 51 healthy females and 83 females with primary breast cancers (eight American Joint Committee on Cancer stage 0, 24 stage I, 27 stage II, 21 stage III, and three stage IV) were assessed preoperatively. Serum DNA integrity was assessed by fragment length-dependent quantitative real-time polymerase chain reaction of ALU DNA repeats. Mean serum DNA integrity was significantly higher in patients with stage II, III, and IV breast cancers than in healthy females (P = .005, P < .0001, and P = .002, respectively). The receiver operating characteristic (ROC) curve for discriminating patients with stage II or more advanced breast cancers from healthy females had an area under the curve (AUC) of 0.79 (95% CI, 0.70 to 0.86). Mean serum DNA integrity was positively correlated to size of invasive cancers (r = 0.48; P < .0001) and significantly higher in the presence of lymphovascular invasion (LVI; 0.25 +/- 0.02 v 0.17 +/- 0.02; P < .0001) or lymph node (LN) metastasis (0.27 +/- 0.02 v 0.14 +/- 0.02; P < .0001). The ROC curve for discriminating LN metastasis had an AUC of 0.81 (95% CI, 0.72 to 0.89). Serum DNA integrity and LVI were significant for predicting LN metastasis in a multivariate analysis (P = .0002 and P < .0001, respectively). Integrity of serum circulating DNA is a promising molecular biomarker for detecting breast cancer tumor progression and regional LN metastases.

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Increased plasma DNA integrity in cancer patients.

Richard Roden, Michael R Bristow, Chien-Jui Cheng … (2003)

Tumor-released DNA in blood represents a promising biomarker for cancer detection. It has been postulated that tumor necrosis causes release of DNA of varying sizes, which contrasts apoptosis in normal tissue that releases smaller and more uniform DNA fragments. To test the hypothesis that increased DNA integrity, i.e., a longer DNA strand, is a tumor-associated marker in plasma, we determined the genomic DNA integrity index in plasma DNA using real-time PCR assays. A DNA integrity index and DNA concentration in plasma were determined in 61 patients with gynecological and breast cancers and 65 female patients without neoplastic diseases. We found that the area under the receiver-operating characteristic curve for DNA integrity index was 0.911 for cancer versus nonneoplastic patients. Given 100% specificity, the highest sensitivity achieved in detecting the cancer group was 62% (95% confidence interval = 0.50-0.74) at the index cutoff of 0.59. Fifty percent of stage I cancers had a DNA integrity index above this cutoff. All 11 patients with benign adnexal masses that clinically can be confused with malignant gynecological neoplasms demonstrated DNA integrity index < 0.59. Our findings suggest that increased DNA integrity in plasma DNA is associated with cancer, and measurement of DNA integrity may provide a simple and inexpensive measure for cancer detection.

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Author and article information

Journal

Journal ID (nlm-ta): J Cancer

Journal ID (iso-abbrev): J Cancer

Journal ID (publisher-id): jca

Title: Journal of Cancer

Publisher: Ivyspring International Publisher (Sydney )

ISSN (Electronic): 1837-9664

Publication date Collection: 2016

Publication date (Electronic): 12 August 2016

Volume: 7

Issue: 13

Pages: 1798-1803

Affiliations

[1 ]Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University

Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China.

[2 ]Cancer Research Institute, Central South University

Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, 410078, China.

[3 ]Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, China.

[4 ]State Key Laboratory of Genetic Engineering Fudan University, Shanghai, 200433, China.

Author notes

✉ Corresponding authors: Jian Zhou, Liver Cancer Institute, Zhongshan Hospital, Fudan University, No. 136 Yi Xue Yuan Road, Shanghai 200032, China. Tel: 86-21-64041990; Fax: 86-21-64037181. E-mail: zhou.jian@ 123456zs-hospital.sh.cn ; or Xin-Rong Yang, Liver Cancer Institute, Zhongshan Hospital, Fudan University, No. 136 Yi Xue Yuan Road, Shanghai 200032, China. Tel: 86-21-64041990; Fax: 86-21-64037181. E-mail: yang.xinrong@ 123456zs-hospital.sh.cn .

# co-first authors

Competing Interests: The authors have declared that no competing interest exists.

Article

Publisher ID: jcav07p1798

DOI: 10.7150/jca.15618

PMC ID: 5039362

PubMed ID: 27698918

SO-VID: 4a22e467-0fac-437d-9360-43e8dd70738c

Copyright © © Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions.

Plasma Circulating Cell-free DNA Integrity as a Promising Biomarker for Diagnosis and Surveillance in Patients with Hepatocellular Carcinoma

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Most cited references 21

Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients.

Prediction of breast tumor progression by integrity of free circulating DNA in serum.

Increased plasma DNA integrity in cancer patients.

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