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.


CONCLUSIONS
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.
Chang
Hsueh-Wei
HW
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Lee
Shing M
SM
Goodman
Steven N
SN
Singer
Gad
G
Cho
Sarah K R
SK
Sokoll
Lori J
LJ
Montz
Fredrick J
FJ
Roden
Richard
R
Zhang
Zhen
Z
Chan
Daniel W
DW
Kurman
Robert J
RJ
Shih
Ie-Ming
IeM
D000328:Adult; D000368:Aged; D022981:Allelic Imbalance; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics*; D018394:CA-125 Antigen / Q000097:blood*; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D012372:ROC Curve; D012680:Sensitivity and Specificity
D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D017931:DNA Primers; D004273:DNA, Neoplasm