Cellular origins and evolutionary dynamics of plasma cfDNA in solid tumors: integrating germline, tumor-derived, and hematopoietic variation for MRD and treatment guidance.
- 1Department of Clinical Laboratory, Beijing Anzhen Nanchong Hospital of Capital Medical University and Nanchong Central Hospital, Nanchong, Sichuan, China.
- 2Department of Blood Transfusion, Beijing Anzhen Nanchong Hospital of Capital Medical University and Nanchong Central Hospital, Nanchong, Sichuan, China.
- 3Department of Clinical Laboratory, Nanchong Hospital of Traditional Chinese Medicine, Nanchong, Sichuan, China.
Abstract
Plasma cell-free DNA (cfDNA) is a heterogeneous and rapidly changing biological pool derived from malignant cells, normal tissues, and hematopoietic cells. The abundance and molecular composition of circulating tumor DNA (ctDNA) are determined not only by tumor burden but also by tissue architecture, vascular access, cell-death programs, chromatin organization, nuclease processing, systemic clearance, treatment exposure, and clonal evolution. These biological determinants shape the mutation, methylation, fragmentation, nucleosomal, and temporal features exploited by contemporary liquid-biopsy assays. Accurate clinical interpretation therefore requires both sensitive detection and reliable source attribution, particularly the distinction of tumor-derived variants from constitutional germline alterations and clonal hematopoiesis. In this review, we integrate the biological origins and processing of plasma cfDNA with analytical strategies for low-tumor-fraction detection and critically evaluate the evidence supporting postoperative molecular residual disease (MRD), recurrence surveillance, treatment-response assessment, resistance monitoring, and ctDNA-guided therapy across solid tumors. Particular emphasis is placed on distinguishing prognostic validity, treatment-predictive value, and demonstrated clinical utility. Current evidence is strongest in colorectal cancer and, more recently, ctDNA-selected urothelial cancer, whereas routine ctDNA-directed intervention in resected non-small cell lung cancer and breast cancer remains insufficiently validated. By linking cfDNA biology to an explicit hierarchy of clinical evidence, this review defines both the established applications and the major limitations that must be addressed before broader implementation of ctDNA-guided precision oncology.
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BibTeX
@article{zhao2026cellular,
title = {{Cellular origins and evolutionary dynamics of plasma cfDNA in solid tumors: integrating germline, tumor-derived, and hematopoietic variation for MRD and treatment guidance.}},
author = {Quanneng Zhao and Chunlei Wu and Xiao Huang and Miyuan Yang and Bing Zhang},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1928945},
url = {https://europepmc.org/article/MED/42953478},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cellular origins and evolutionary dynamics of plasma cfDNA in solid tumors: integrating germline, tumor-derived, and hematopoietic variation for MRD and treatment guidance.
AU - Quanneng Zhao
AU - Chunlei Wu
AU - Xiao Huang
AU - Miyuan Yang
AU - Bing Zhang
PY - 2026
DA - 2026/10/14
JO - Frontiers in cell and developmental biology
DO - 10.3389/fcell.2026.1928945
UR - https://europepmc.org/article/MED/42953478
AB - Plasma cell-free DNA (cfDNA) is a heterogeneous and rapidly changing biological pool derived from malignant cells, normal tissues, and hematopoietic cells. The abundance and molecular composition of circulating tumor DNA (ctDNA) are determined not only by tumor burden but also by tissue architecture, vascular access, cell-death programs, chromatin organization, nuclease processing, systemic clearance, treatment exposure, and clonal evolution. These biological determinants shape the mutation, methylation, fragmentation, nucleosomal, and temporal features exploited by contemporary liquid-biopsy assays. Accurate clinical interpretation therefore requires both sensitive detection and reliable source attribution, particularly the distinction of tumor-derived variants from constitutional germline alterations and clonal hematopoiesis. In this review, we integrate the biological origins and processing of plasma cfDNA with analytical strategies for low-tumor-fraction detection and critically evaluate the evidence supporting postoperative molecular residual disease (MRD), recurrence surveillance, treatment-response assessment, resistance monitoring, and ctDNA-guided therapy across solid tumors. Particular emphasis is placed on distinguishing prognostic validity, treatment-predictive value, and demonstrated clinical utility. Current evidence is strongest in colorectal cancer and, more recently, ctDNA-selected urothelial cancer, whereas routine ctDNA-directed intervention in resected non-small cell lung cancer and breast cancer remains insufficiently validated. By linking cfDNA biology to an explicit hierarchy of clinical evidence, this review defines both the established applications and the major limitations that must be addressed before broader implementation of ctDNA-guided precision oncology.
SN - 2296-634X
ER -