Cell-free DNA concentration and fragment size as a biomarker for prostate cancer

Abstract

Prostate cancer is the most commonly diagnosed neoplasm in American men. Although existing biomarkers may detect localized prostate cancer, additional strategies are necessary for improving detection and identifying aggressive disease that may require further intervention. One promising, minimally invasive biomarker is cell-free DNA (cfDNA), which consist of short DNA fragments released into circulation by dying or lysed cells that may reflect underlying cancer. Here we investigated whether differences in cfDNA concentration and cfDNA fragment size could improve the sensitivity for detecting more advanced and aggressive prostate cancer. This study included 268 individuals: 34 healthy controls, 112 men with localized prostate cancer who underwent radical prostatectomy (RP), and 122 men with metastatic castration-resistant prostate cancer (mCRPC). Plasma cfDNA concentration and fragment size were quantified with the Qubit 3.0 and the 2100 Bioanalyzer. The potential relationship between cfDNA concentration or fragment size and localized or mCRPC prostate cancer was evaluated with descriptive statistics, logistic regression, and area under the curve analysis with cross-validation. Plasma cfDNA concentrations were elevated in mCRPC patients in comparison to localized disease (OR_5ng/mL = 1.34, P = 0.027) or to being a control (OR_5ng/mL = 1.69, P = 0.034). Decreased average fragment size was associated with an increased risk of localized disease compared to controls (OR_5bp = 0.77, P = 0.0008). This study suggests that while cfDNA concentration can identify mCRPC patients, it is unable to distinguish between healthy individuals and patients with localized prostate cancer. In addition to PSA, average cfDNA fragment size may be an alternative that can differentiate between healthy individuals and those with localized disease, but the low sensitivity and specificity results in an imperfect diagnostic marker. While quantification of cfDNA may provide a quick, cost-effective approach to help guide treatment decisions in advanced disease, its use is limited in the setting of localized prostate cancer.

Figure 1

Distribution of plasma cfDNA concentration in healthy individuals, patients with localized disease, and patients with mCRPC. Boxplots and points identify the minimum, interquartile range, median, and maximum values for each group. The Mann–Whitney test was applied to test differences in cfDNA concentration between groups. *** P < 0.0001.

Figure 2

Receiver operating characteristic (ROC) curves for cfDNA concentration comparison between (A) healthy individuals and mCRPC, and (B) patients with localized disease and mCRPC. Area under the curve (AUC) and 95% CI were estimated with k-fold cross-validation and bootstrap resampling.

Figure 3

Distribution of average fragment size in healthy individuals and patients with localized disease (P = 0.0009). Boxplots and points identify the minimum, interquartile range, median, and maximum values for each group. A Mann–Whitney U-test was performed to test the difference in cfDNA fragment size.