Somatic mutations accumulate in normal tissues as a function of time. The great majority of these mutations have no effect on fitness, so selection does not act upon them. Rarely, a mutation will arise that confers a selective growth advantage to the cell in which it occurs. Such a mutation would allow that cell and its progeny, referred to as a “clone,” to progressively expand over time. This is now appreciated to occur in a number of tissues, particularly in aged individuals. When this happens in a hematopoietic stem cell (HSC), “clonal hematopoiesis” may result if the mutated clone contributes to the production of a substantial proportion of mature blood cells.

Mutations in genes involved in epigenetic regulation (DNMT3A, TET2, ASXL1) account for the majority of mutation-driven clonal hematopoiesis in humans. These mutations are rare in the young but highly prevalent in the elderly, with between 10 and 20% of those older than age 70 harboring a clone of appreciable size. These individuals usually have only a single driver gene mutated, in contrast to individuals with frank malignancy, where there might be several such mutations. Clonal hematopoiesis of indeterminate potential (CHIP) is a clinical entity defined by the presence of a cancer-associated clonal mutation in at least 4% of nucleated blood cells of individuals without frank neoplasia.

Large-scale genetic studies have revealed the prevalence and clinical associations of somatic, clonal mutations in blood cells of individuals without hematologic malignancies. One expected consequence of harboring a cancer-associated mutation in blood is an increased risk of developing an overt hematologic malignancy, as the initiating mutation may progress to cancer if additional cooperating mutations are acquired. Indeed, recent studies have demonstrated that CHIP is associated with an increased risk of developing blood cancers, confirming that it is a bona fide premalignant state. Individuals with CHIP progress to malignancy at a rate of about 0.5 to 1% per year. Factors that influence the likelihood of progression to malignancy include the size of the clone, the number of mutations, and the specific gene or genes that are mutated.

The process of precancerous clonal expansion likely occurs in all mitotically active tissues, as has recently been shown in studies of human skin and esophagus. Clonal hematopoiesis may also be relevant to phenotypes apart from malignancy. The blood stem cells that harbor the mutations give rise to immune cells such as granulocytes, monocytes, macrophages, and lymphocytes. As these cells reside in nearly all tissues, mutations that alter their function could have a variety of phenotypic consequences. For example, recent studies have suggested that CHIP is associated with an increased risk of all-cause mortality and an increased risk of cardiovascular diseases such as myocardial infarction, stroke, and venous thrombosis. The risk appears to be substantial, as the hazard ratio associated with CHIP is as great as or greater than many commonly assessed risk factors for cardiovascular disease, such as smoking, cholesterol levels, and high blood pressure. Mouse models that carry some of the common CHIP mutations display enhanced atherosclerosis, consistent with a causal relationship between the mutations and the disease. At a mechanistic level, the mutations may amplify the inflammatory response by the innate immune system, a known contributing factor in the development of atherosclerosis. CHIP may be a general factor underlying age-related inflammation and could potentially influence several diseases of aging.

Although the …