Association of the Immediate Perioperative Dynamics of Circulating DNA Levels and Neutrophil Extracellular Traps Formation in Cancer Patients

Life Sciences Medicine Basic Medical Sciences Oncology Immunology
circulating DNA perioperative period neutrophil extracellular traps neutrophil elastase myeloperoxidase minimal residual disease

Academic Background

Circulating DNA (cirdna) has garnered significant attention in recent years for its potential in tumor diagnosis, particularly in the field of liquid biopsy. cirdna not only aids in detecting tumor gene mutations but also plays a crucial role in treatment monitoring, cancer recurrence surveillance, and cancer screening. However, research on the dynamic changes and origins of cirdna during the perioperative period remains limited. Surgery, as a common cancer treatment, often involves tissue damage, inflammatory responses, and immune cell activation, which may lead to increased cirdna release. Additionally, neutrophil extracellular traps (nets), an essential component of the immune system, may play a role in post-surgical inflammatory responses and are closely related to cirdna release.

This study aims to explore the dynamic changes of cirdna and nets in cancer patients during the perioperative period, particularly whether cirdna release is associated with nets formation. By analyzing plasma levels of cirdna and nets markers, the research team hopes to uncover the mechanisms of cirdna release post-surgery and provide new biomarkers for post-operative management in cancer patients.

Source of the Paper

This paper was co-authored by Andrei Kudriavtsev, Brice Pastor, Alexia Mirandola, and others from the Institut de Recherche en Cancérologie de Montpellier, Université de Montpellier, and Centre Hospitalo-Universitaire de Nîmes, among other institutions. The paper was published on March 27, 2024, in the journal Precision Clinical Medicine, with the DOI 10.1093/pcmedi/pbae008.

Research Process

Study Subjects and Sample Collection

The study included 29 patients with colon, prostate, and breast cancer, as well as 114 healthy individuals (hi) as a control group. Blood samples were collected from patients at multiple time points, ranging from 24 hours before surgery to 72 hours after surgery, totaling nine time points. All plasma samples were immediately centrifuged and stored at -80°C for subsequent analysis.

Circulating DNA Extraction and Quantification

cirdna (including nuclear DNA and mitochondrial DNA) was extracted from plasma using the Maxwell RSC ccfDNA Plasma Kit. The extracted cirdna was then quantified using real-time quantitative PCR (qPCR). Nuclear DNA (cir-ndna) and mitochondrial DNA (cir-mtdna) were amplified and quantified using specific fragments of the KRAS gene and mitochondrial cytochrome oxidase II gene (mt-co3), respectively.

Neutrophil Extracellular Trap Marker Detection

The study also measured two protein markers of nets: myeloperoxidase (mpo) and neutrophil elastase (ne). These markers were quantified using enzyme-linked immunosorbent assay (ELISA).

Data Analysis

Spearman correlation analysis was used to assess the relationship between cirdna and nets markers. The Mann-Whitney U test was employed to compare differences between cancer patients and healthy individuals.

Key Findings

Dynamic Changes of cirdna During the Perioperative Period

The results showed a significant increase in cirdna levels post-surgery, peaking at the end of the procedure. In colon and prostate cancer patients, cirdna levels continued to rise within 72 hours after surgery, while in breast cancer patients, cirdna levels remained relatively stable. Compared to healthy individuals, cirdna levels in cancer patients were significantly higher both before and after surgery.

Association Between nets Markers and cirdna

nets markers (mpo and ne) also increased significantly post-surgery and were positively correlated with cirdna levels. This association was particularly strong in colon cancer patients. In contrast, the correlation between cirdna and nets markers was weaker in prostate and breast cancer patients.

Dynamic Changes of Mitochondrial DNA

Mitochondrial DNA (cir-mtdna) also increased post-surgery, but its dynamic changes differed from those of cirdna. In prostate cancer patients, cir-mtdna levels rose significantly within 24 hours after surgery, while in colon and breast cancer patients, cir-mtdna levels remained relatively stable. Additionally, the association between cir-mtdna and nets markers was weak, suggesting that its release mechanism may differ from that of cirdna.

Fragmentation Analysis

Through shallow whole genome sequencing (swgs), the study found increased fragmentation of cirdna post-surgery, particularly in colon cancer patients. This indicates that post-surgical cirdna release may be related to the degradation of nets.

Conclusion

This study is the first to reveal the dynamic changes of cirdna and nets in cancer patients during the perioperative period and confirms the significant role of nets in post-surgical cirdna release. The findings suggest that the increase in cirdna post-surgery primarily originates from the degradation of nets, particularly in colon cancer patients. This discovery provides a new explanation for the source of post-surgical cirdna and offers potential biomarkers for post-operative management in cancer patients.

Research Highlights

  1. First Perioperative cirdna Dynamics Study: This study is the first to systematically track cirdna and nets during the perioperative period, filling a gap in this field of research.
  2. Association Between nets and cirdna: The study confirms the significant role of nets in post-surgical cirdna release, providing a new explanation for the source of cirdna.
  3. Differences Among Cancer Types: The study found significant differences in the dynamic changes of cirdna and nets among different cancer types during the perioperative period, offering a basis for personalized post-operative management.

Research Value

This study not only provides a new explanation for the source of post-surgical cirdna but also offers potential biomarkers for post-operative management in cancer patients. By monitoring the dynamic changes of cirdna and nets, clinicians can better assess post-surgical inflammatory responses and recurrence risks, thereby developing more effective treatment plans. Furthermore, this study provides valuable reference data for future perioperative research.