Assessment of plasma DNA levels, allelic imbalance, and CA 125 as diagnostic tests for cancer.

BACKGROUND Allelic imbalance (AI), the loss or gain of chromosomal regions, is found in many cancers. AI can be detected in genomic tumor DNA released into the blood after necrosis or apoptosis. We evaluated plasma DNA concentration, allelic status in plasma DNA, and serum CA 125 level as screening tests for ovarian and other cancers. METHODS Plasma samples were obtained from 330 women (44 normal healthy control individuals, 122 patients with various cancers, and 164 control patients with non-neoplastic diseases). Plasma DNA concentration was determined in all samples. Allelic status was determined by digital single nucleotide polymorphism (SNP) analysis with eight SNP markers in plasma DNA from 54 patients with ovarian cancer and 31 control patients. CA 125 was determined in 63 samples. Receiver-operating characteristic (ROC) curves were plotted, and the areas under the ROC curves--a measure of the overall ability of a diagnostic test with multiple cutoffs to distinguish between diseased and nondiseased individuals--were determined. RESULTS The area under the ROC curve for plasma DNA concentration was 0.90 for patients with neoplastic disease versus healthy control individuals and 0.74 for patients with neoplastic diseases versus control patients with non-neoplastic diseases. For control subjects given a specificity of 100% (95% confidence interval [CI] = 92% to 100%), the highest sensitivity achieved was 57% (95% CI = 49% to 67%). AI in at least one SNP was found in 87% (95% CI = 60% to 98%) of patients with stage I/II ovarian cancer and 95% (95% CI = 83% to 99%) of patients with stage III/IV ovarian cancer, but AI was not found in 31 patients with non-neoplastic diseases (specificity = 100%, 95% CI = 89% to 100%). The area under the ROC curve assessing AI was 0.95. Combining the serum CA 125 level with the plasma DNA concentration increased the area under the ROC curve from 0.78 (CA 125 alone) to 0.84. CONCLUSION Plasma DNA concentration may not be sensitive or specific enough for cancer screening or diagnosis, even when combined with CA 125. AI was detected with high specificity in plasma DNA from patients with ovarian cancer and should be studied further as a screening tool.

[1]  H. Mulcahy,et al.  Detection of Circulating Tumour DNA in the Blood (Plasma/Serum) of Cancer Patients , 2004, Cancer and Metastasis Reviews.

[2]  Hsueh-Wei Chang,et al.  Detection of allelic imbalance in ascitic supernatant by digital single nucleotide polymorphism analysis. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[3]  E. Diamandis,et al.  Tumor Markers: Physiology, Pathobiology, Technology, and Clinical Applications , 2002 .

[4]  F. Bischoff,et al.  Somatic DNA alterations in endometriosis: high frequency of chromosome 17 and p53 loss in late-stage endometriosis. , 2002, Journal of reproductive immunology.

[5]  I. Shih,et al.  Diverse tumorigenic pathways in ovarian serous carcinoma. , 2002, The American journal of pathology.

[6]  C. Hopenhayn-Rich,et al.  Heterogeneity of Ovarian Cancer: Relationships Among Histological Group, Stage of Disease, Tumor Markers, Patient Characteristics, and Survival , 2002, Cancer investigation.

[7]  P. Paley.  Ovarian cancer screening: are we making any progress? , 2001, Current opinion in oncology.

[8]  T. A. Taton.  Nanotechnology: Boning up on biology , 2001, Nature.

[9]  D. Birnbaum,et al.  High frequency of allelic imbalance at regions of chromosome arm 8p in ovarian carcinoma. , 2001, Cancer genetics and cytogenetics.

[10]  Jose M. Silva,et al.  Heterogeneous tumor clones as an explanation of discordance between plasma DNA and tumor DNA alterations , 2001, Genes, chromosomes & cancer.

[11]  K. Kinzler,et al.  Top-down morphogenesis of colorectal tumors , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[12]  K. Kinzler,et al.  Mechanisms underlying losses of heterozygosity in human colorectal cancers , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[13]  F. O. Fackelmayer,et al.  DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. , 2001, Cancer research.

[14]  S. Goodman,et al.  Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. , 2001, Cancer research.

[15]  D. Spandidos,et al.  Microsatellite DNA assays reveal an allelic imbalance in p16(Ink4), GALT, p53, and APOA2 loci in patients with endometriosis. , 2001, Fertility and sterility.

[16]  Michael A. Choti,et al.  Counting alleles reveals a connection between chromosome 18q loss and vascular invasion , 2001, Nature Biotechnology.

[17]  P. Buamah.  Benign conditions associated with raised serum CA‐125 concentration , 2000, Journal of surgical oncology.

[18]  M Misakian,et al.  Driven DNA transport into an asymmetric nanometer-scale pore. , 2000, Physical review letters.

[19]  G. Rustin,et al.  Role of tumour markers in monitoring epithelial ovarian cancer , 2000, British Journal of Cancer.

[20]  I. Petersen,et al.  Detection of Microsatellite Alterations in the DNA Isolated from Tumor Cells and from Plasma DNA of Patients with Lung Cancer , 2000, Annals of the New York Academy of Sciences.

[21]  J. Jen,et al.  An Overview on the Isolation and Analysis of Circulating Tumor DNA in Plasma and Serum , 2000, Annals of the New York Academy of Sciences.

[22]  T. Walsh,et al.  Microsatellite alterations plasma DNA of primary breast cancer patients. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[23]  P. Laurent-Puig,et al.  Detection of plasma tumor DNA in head and neck squamous cell carcinoma by microsatellite typing and p53 mutation analysis. , 2000, Cancer research.

[24]  K. Kinzler,et al.  Genetic instability and darwinian selection in tumours. , 1999, Trends in cell biology.

[25]  E. Zabarovsky,et al.  Loss of heterozygosity in tumor cells requires re‐evaluation: the data are biased by the size‐dependent differential sensitivity of allele detection , 1999, FEBS letters.

[26]  U. Pastorino,et al.  Detection of microsatellite alterations in plasma DNA of non-small cell lung cancer patients: a prospect for early diagnosis. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[27]  R. Lidereau,et al.  Somatic genetic alterations (loh) in benign, borderline and invasive ovarian tumours: Intratumoral molecular heterogeneity , 1999, International journal of cancer.

[28]  M. Dietel,et al.  Microsatellite alterations in serum DNA of patients with colorectal cancer. , 1999, Laboratory investigation; a journal of technical methods and pathology.

[29]  P. Burns,et al.  Molecular detection of tumour DNA in serum and peritoneal fluid from ovarian cancer patients , 1999, British Journal of Cancer.

[30]  Jose M. Silva,et al.  Presence of tumor DNA in plasma of breast cancer patients: clinicopathological correlations. , 1999, Cancer research.

[31]  R. Turner,et al.  Plasma DNA microsatellites as tumor-specific markers and indicators of tumor progression in melanoma patients. , 1999, Cancer research.

[32]  J. Herman,et al.  Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients. , 1999, Cancer research.

[33]  K. Kinzler,et al.  Genetic instabilities in human cancers , 1998, Nature.

[34]  K. Miller,et al.  Microsatellite analysis of plasma DNA from patients with clear cell renal carcinoma. , 1998, Cancer research.

[35]  G. I. Obrams,et al.  Epidemiology and risk assessment for ovarian cancer. , 1998, Seminars in oncology.

[36]  A. Kurt,et al.  Microsatellite alterations in plasma DNA of small cell lung cancer patients , 1996, Nature Medicine.

[37]  David Sidransky,et al.  Microsatellite alterations in serum DNA of head and neck cancer patients , 1996, Nature Medicine.

[38]  D. Pinkel,et al.  Genetic analysis of benign, low-grade, and high-grade ovarian tumors. , 1995, Cancer research.

[39]  P. Dombernowsky,et al.  Tumor markers in the management of patients with ovarian cancer. , 1995, Cancer treatment reviews.

[40]  L. Hartmann,et al.  Comparison of loss of heterozygosity patterns in invasive low-grade and high-grade epithelial ovarian carcinomas. , 1993, Cancer research.

[41]  L. Hartmann,et al.  Human epithelial ovarian cancer allelotype. , 1993, Cancer research.

[42]  S. Nozawa.  [Tumor markers of ovarian cancer]. , 1992, Rinsho byori. The Japanese journal of clinical pathology.

[43]  C. Perez,et al.  Principles and Practice of Gynecologic Oncology , 1992 .

[44]  M. Lahousen.  [Tumor markers in ovarian cancer]. , 1987, Jugoslavenska ginekologija i perinatologija.

[45]  T. P. Dryja,et al.  Expression of recessive alleles by chromosomal mechanisms in retinoblastoma , 1983, Nature.

[46]  B. Shapiro,et al.  Free DNA in the serum of cancer patients and the effect of therapy. , 1977, Cancer research.