CHIP Happens: Clonal Hematopoiesis of Indeterminate Potential and Its Relationship to Solid Tumors

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the expansion of hematopoietic cells harboring leukemia-associated somatic mutations in otherwise healthy people and occurs in at least 10% of adults over 70. It is well established that people with CHIP have increased rates of hematologic malignancy, increased risk of cardiovascular disease, and worse all-cause mortality compared with those without CHIP. Despite recent advancements in understanding CHIP as it relates to these known outcomes, much remains to be learned about the development and role of CHIP in other disease states. Emerging research has identified high rates of CHIP in patients with solid tumors, driven in part by oncologic therapy, and revealed associations between CHIP and differential outcomes in both solid tumors and other diseases. Recent studies have demonstrated that CHIP can contribute to dysregulated inflammatory signaling in multiple contexts, underscoring the importance of interrogating how CHIP might alter tumor immunology. Here, we review the role of CHIP mutations in clonal expansion of hematopoietic cells, explore the relationship between CHIP and solid tumors, and discuss the potential roles of CHIP in inflammation and solid tumor biology.

Figure 1.

Schematic of CHIP development and presence of immune cells with CHIP in circulation and in solid tumors. (a) Hematopoietic stem cells, like other tissues, acquire somatic mutations with age and exposure to smoking and genotoxic stress. While some of these mutations are neutral, others promote clonal expansion and become overrepresented. CHIP mutations are observed in genes associated with myeloid neoplasms, with some mutations more common than others. The list provided is not comprehensive. (b) Hematopoietic cells with CHIP are present in circulation and can infiltrate the tumor microenvironment. Though the effect of CHIP on dysregulated immune cell function and on solid tumor biology requires additional research, CHIP has been associated with differential clinical outcomes that are relevant to patients with primary non-hematologic cancers. Some of these outcomes are due to CHIP clones circulating in the blood (pink boxes), while others are due CHIP clones in the tumor microenvironment (orange boxes). (Figure created with BioRender.com.)