Clinical Relevance of Circulating Nucleosomes in Cancer

Abstract

Nucleosomes, complexes of DNA and histone proteins, are released during cell death into the blood circulation. Elevated serum and plasma levels have been found in various forms of cancer, but also in autoimmune diseases and acute situations such as stroke, trauma, and during sepsis. Here, the clinical relevance of circulating nucleosomes for diagnosis, staging, prognosis, and therapeutic monitoring of cancer is reviewed. Several studies have shown that levels of nucleosomes are significantly higher in serum and plasma of cancer patients in comparison to healthy controls. However, because of elevations of nucleosome levels in patients with benign diseases relevant for differential diagnosis, they are not suitable for cancer diagnosis. Concerning tumor staging, nucleosome levels correlate with tumor stage and presence of metastases in gastrointestinal cancer, but not in other tumor types. Prognostic value of circulating nucleosomes is found in lung cancer in univariate analyses, but not in multivariate analyses. Circulating nucleosomes are most informative for the monitoring of cytotoxic therapy. Strongly decreasing levels are mainly found in patients with remission of disease, whereas constantly high or increasing values are associated with progressive disease during chemo- and radiotherapy. In addition, therapy outcome is already indicated by the nucleosomal course during the first week of chemo- and radiotherapy in patients with lung, pancreatic, and colorectal cancer as well as in hematologic malignancies. Despite their non-tumor-specificity, kinetics of nucleosomes are valuable markers for the early estimation of therapeutic efficacy and may be helpful to adapting early cancer therapy in the future.

Next Generation Sequencing of Serum Circulating Nucleic Acids from Patients with Invasive Ductal Breast Cancer Reveals Differences to Healthy and Nonmalignant Controls

“…The origin of serum DNA sequences is controversial. Generally, cell-free DNA in the blood is associated with histones and it is assumed that these circulating nucleosomes originate from apoptotic or necrotic cells in the body, and that the protein-bound DNA is protected from digestion by nucleases (19). Our sequencing approach revealed differences in the relative amounts of different repetitive elements that might reflect a differential nucleosome positioning in the genome of the cancerous cells.…”

“…Measurements of absolute levels of CNAs have been suggested for the diagnosis (13) and prognosis (14) of breast and lung cancer (15). The general diagnostic value of simple quantitative measures of CNA, however, is controversial because nonspecific CNA elevations are seen in patients with benign diseases (16)(17)(18)(19). Cancer-specific DNA perturbations such as microsatellite instability, mutations, sequence length, and promoter methylation patterns detected in serum/plasma have been proposed for the diagnosis and clinical assessment of cancer treatment (20).…”

Evaluation of Circulating Tumor Cells and Serological Cell Death Biomarkers in Small Cell Lung Cancer Patients Undergoing Chemotherapy

“…Elevated levels of circulating free DNA are detectable in cancer patients including those with SCLC 29 and several studies have supported a role for nDNA in monitoring and predicting clinical outcome. 30 In a recent study of 128 patients with SCLC the utility of nDNA measured immediately before the first three cycles of therapy was compared with a panel of other putative SCLC biomarkers (CYFRA21-1, CEA, NSE, and proGRP). They found that falling levels of all biomarkers, including nDNA, at the start of cycle 2 could be used with reasonable sensitivity and specificity to predict early response to therapy.…”

Generation of blood circulating DNA: the sources, peculiarities of circulation and structure

“…Увеличение количества клеток, вступивших в апоптоз или некроз, приводит к повышению количества нуклеосом в циркуляции [55]. Доказательством этого факта является возрастание концентрации нуклеосом как в плазме, так и в сыворотке крови при различных формах онкологических заболеваний, травмах и сепсисе по сравнению с плазмой/сывороткой крови здоровых доноров [56]. Концентрация нуклеосом в сыворотке не является специфическим признаком [57], концентрация нуклеосом коррелирует со стадией онкологического заболевания и присутствием метастазов только у больных раком желудочно-кишечного тракта [56,58].…”