Somatic mosaicism arises from random mutational damage to stem cells and progenitor cells. Daughter somatic cells resulting from mutated cells also bear these mutations, and so a pattern of differently mutated somatic cell populations spreads throughout a tissue over years and decades. This is thought to be a mechanism by which nuclear DNA damage can give rise to some meaningful degree of dysfunction beyond cancer risk. Otherwise, one must accept that near all mutations (a) affect few cells, as somatic cells are limited in their ability to replicate, and (b) occur in cells that will be destroyed on some timescale, as they hit the Hayflick limit. Further, the vast majority of somatic cell mutations occur in unused areas of DNA, and should not change cell behavior via altered or missing proteins.
Recently, researchers have suggested that some forms of nuclear DNA damage cause characteristic age-related changes in gene expression regardless of where they occur and whether they are successfully repaired, which may turn out to be the more important issue deriving from DNA damage. With regard to changes that do affect cell function and then spread from stem cells into a sizable fraction of cells in a tissue, evidence is sparse when it comes to clear connections between this somatic mosaicism and specific issues in aging, however. That said, clonal hematopoiesis of indeterminate potential (CHIP) is a form of somatic mosaicism specific to the immune system, and one of the few types of somatic mosaicism for which data does exists to link the process to detrimental consequences in later life. Thus researchers are interested in expanding this foothold, to better determine when CHIP can be problematic versus benign.
Clonal hematopoiesis (CH), where hematopoietic stem and progenitor cell (HSPC) clones and their progeny expand in the circulating blood cell population, occurs following the acquisition of somatic driver mutations. Individuals diagnosed with clonal hematopoiesis of indeterminate potential (CHIP) carry somatic mutations in hematological malignancy-associated driver genes, historically at or above a variant allele frequency of 2%, but do not exhibit abnormal blood cell counts or any other symptoms of hematologic disease. However, CHIP is associated with moderately increased risk of hematological cancer, and a greater likelihood of cardiovascular disease and pulmonary disease.
Recent advances in the resolution of high-throughput sequencing experiments suggest CHIP is much more prevalent in the population than once thought, particularly among those aged 60 and over. While CHIP does elevate the risk of eventual hematological malignancy, only one in ten individuals with CHIP will receive such a diagnosis; the problem lies in the continued difficulty in accurately separating the 10% of CHIP patients who are most likely to be in a pre-malignant state from those who are not, given the heterogeneity of this condition and the etiology of the associated hematological cancers. Concerns over the risk of eventual malignancies must be balanced with growing recognition of CH as common age-dependent occurrence, and efforts to better characterize and differentiate oncogenic clonal expansion from that which is much more benign.
In this review, we discuss evolutionary dynamics of CH and CHIP, the relationship of CH to aging and inflammation, and the role of the epigenome in promoting potentially pathogenic or benign cellular trajectories. We outline molecular mechanisms that may contribute to heterogeneity in the etiology of CHIP and incidence of malignant disease among individuals. Finally, we discuss epigenetic markers and modifications for CHIP detection and monitoring with potential for translational applications and clinical utility in the near future.
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