Clinical significance of cell-free DNA as a prognostic biomarker in patients with diffuse large B-cell lymphoma

Abstract

Background Cell-free DNA (cfDNA) has the potential to serve as a non-invasive prognostic biomarker in some types of neoplasia. The investigation of plasma concentration of cfDNA may reveal its use as a valuable biomarker for risk stratification of diffuse large B-cell lymphoma (DLBCL). The present prognostic value of plasma cfDNA has not been widely confirmed in DLBCL subjects. Here, we evaluated cfDNA plasma concentration and assessed its potential prognostic value as an early DLBCL diagnostic tool. Methods cfDNA concentrations in plasma samples from 40 patients with DLBCL during diagnosis and of 38 normal controls were determined with quantitative polymerase chain reaction (qPCR) for the multi-locus L1PA2 gene. Results Statistically significant elevation in plasma cfDNA concentrations was observed in patients with DLBCL as compared to that in normal controls ( P <0.05). A cutoff point of 2.071 ng/mL provided 82.5% sensitivity and 62.8% specificity and allowed successful discrimination of patients with DLBCL from normal controls (area under the curve=0.777; P =0.00003). Furthermore, patients with DLBCL showing higher concentrations of cfDNA had shorter overall survival (median, 9 mo; P =0.022) than those with lower cfDNA levels. In addition, elevated cfDNA concentration was significantly associated with age, B-symptoms, International Prognostic Index (IPI) score, and different stages of disease (all P <0.05). Conclusion Quantification of cfDNA with qPCR at the time of diagnosis may allow identification of patients with high cfDNA concentration, which correlates with aggressive clinical outcomes and adverse prognosis.

Clinical Application of Liquid Biopsy in Non-Hodgkin Lymphoma

“…Rivas et al (59), Sun et al (37), and Bohers et al (61) have shown that the detection of cfDNA/ctDNA in DLBCL is related to LDH levels. In contrast, Hur et al (33) and Eskandari et al (34) found no strong correlations between serum LDH and cfDNA in DLBCL. The relationship between cfDNA and Ki-67 is also unclear.…”

“…Currently, the most commonly used methods to detect cfDNA include various types of PCR. Commonly used methods to quantify cfDNA/ ctDNA are Qubit for quantification (33,37) and quantitative PCR (34)(35)(36). Although differences in the detection methods used have resulted in heterogeneity among the cfDNA concentrations reported by different studies, all of these studies have reached the conclusion that cfDNA concentrations in NHL cases are higher than those in normal controls.…”

“…Although tissue biopsies are invasive, a pathological NHL diagnosis based on the histological examination of a tissue biopsy sample remains the “gold standard.” As a noninvasive test, cfDNA assessments are safer and more reproducible than tissue biopsies and are, therefore, likely to become a standardized detection method for disease screening and early diagnosis. Several studies have shown that cfDNA is increased in DLBCL compared with the normal control group, with a sensitivity of 70%–82.5% ( 33 – 35 ) and a specificity of 62.8%–94% ( 34 – 36 ). The median cfDNA concentration has varied across studies, ranging from 11.7–845 ng/ml in DLBCL, 12.4–662 ng/ml in NKTCL, and 12.9–942 ng/ml in TCL ( 33 , 35 – 37 ).…”

Monitoring treatment response and disease progression in myeloma with circulating cell‐free DNA

“…In addition to protein and molecular biomarkers, cell‐free DNA (cfDNA) has gained significance as a potential biomarker for tumor burden in various cancers including myeloma 4,5 . Although cfDNA is an admixture of normal and tumor‐derived DNA (ctDNA), increased concentration of cfDNA is indicative of higher tumor burden and is a prognostic biomarker of survival in many cancers 4,6 . In MM, ctDNA levels increase with disease progression 7 and genomic variations detected in cfDNA have been used to monitor disease status and response to therapy 8‐10 …”

“…indicative of higher tumor burden and is a prognostic biomarker of survival in many cancers. 4,6 In MM, ctDNA levels increase with disease progression 7 and genomic variations detected in cfDNA have been used to monitor disease status and response to therapy. [8][9][10] In this study, we assessed if cfDNA levels are a measure of tumor burden by correlating data from 77 patients with standard clinical biomarkers such as lactate dehydrogenase (LDH), free light chain (FLC) ratio, beta-2-microglobulin (β 2 m), and albumin, in addition to GEP70 risk score.…”