Clonal hematopoiesis of indeterminate potential in metastatic colorectal cancer: bidirectional regulation, systemic selection, and translational strategies

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by the expansion of hematopoietic stem cells harboring somatic mutations in the absence of overt hematological malignancies. Traditionally, CHIP has been viewed either as a driver of systemic inflammation or as a source of false-positive artifacts in liquid biopsy assays for solid tumors. This review systematizes the evidence for a reciprocal pathogenetic link – namely, the distant regulatory influence of metastatic colorectal cancer (mCRC) on the bone marrow microenvironment. We propose a conceptual model of a bidirectional “mCRC ↔ CHIP” interface, delineate the molecular mechanisms governing mutant clone selection under tumor-imposed pressure, and outline strategies to minimize diagnostic errors in circulating tumor DNA analysis.

Metastatic colorectal cancer acts as a systemic regulator of hematopoiesis. Chronic systemic inflammation induced by the secretion of tumor and metastasis mediators (interleukin (IL) 6, tumor necrosis factor α, granulocyte colony-stimulating factor), in combination with persistent oxidative stress, causes replicative exhaustion and apoptosis of normal hematopoietic stem cells. Under these conditions, CHIP clones carrying mutations in genes involved in epigenetic control (TET2, DNMT3A) and DNA damage response (TP53, PPM1D) acquire a selective fitness advantage. In the context of bidirectional regulation, hyperreactive myeloid cells originating from CHIP clones migrate to intestinal and hepatic tissues, where they establish pre-metastatic niches, promote angiogenesis (via vascular endothelial growth factor, matrix metallopeptidase 9), and suppress CD8⁺ T-cell activity (through programmed death ligand 1, indoleamine-2,3-dioxygenase). Standard platinum-based chemotherapy (FOLFOX) acts as an additional catalyst for the iatrogenic selection of TP53/PPM1D clones, whereas primary tumor resection de-escalates the inflammatory pressure on the bone marrow. CHIP compromises the specificity of liquid biopsy by generating false-positive signals for progression (TP53) and resistance (RAS) markers. The gold standard for overcoming this interference is paired buffy coat sequencing combined with fragmentomics-based approaches.

Disruption of the pathological “mCRC ↔ CHIP” axis through anti-cytokine therapy (IL-1β and IL-6 inhibitors) and the integration of onco-hematological monitoring into precision oncology may prevent tumor immune evasion, reduce the risk of secondary leukemias, and improve patient survival outcomes.