Michelle Dotzert, PhD
Somatic mutations are a normal occurrence with aging. While most somatic mutations don’t produce functional effects, some confer a survival or fitness advantage on a cell and lead to clonal expansion, which may precede cancer. Within the hematopoietic system, the clonal expansion of stem cells—clonal hematopoiesis—may precede several hematologic cancers, but has also been observed among individuals with no hematologic malignancy. This condition is referred to as clonal hematopoiesis of indeterminate potential (CHIP), and it is also associated with increased risk of atherosclerosis and cardiovascular disease. CHIP prevalence increases with age, and diagnosis often occurs as a result of DNA testing for other diseases. However, as next generation sequencing (NGS) technologies become increasingly accessible, CHIP screening and monitoring has potential value in the clinical setting.
Discovery of CHIP
In 2014, a study examining highly purified hematopoietic stem cells, progenitor, and mature cell fractions from patients with acute myeloid leukemia provided evidence that the disease progressed form a pre-leukemic hematopoietic stem cell population. Because these pre-leukemic cells contained somatic mutations that conferred repopulation advantages, they could drive clonal expansion and enable the acquisition of secondary mutations leading patients to develop acute myeloid leukemia.
Surprisingly, in this same study, a subset of somatic mutations occurring in the leukemic cells were also observed in normal T cells isolated from peripheral blood samples. Based on the finding, others began to investigate whether such mutations might also be observed in cells from the general population, with no associated malignancy. Analysis of data from whole-exome sequencing of DNA in peripheral-blood cells of 12,380 individuals without cancer or hematologic phenotype revealed clonal hematopoiesis increases with age; clonal hematopoiesis with somatic mutations was observed in 10 percent of the study population over 65 years of age, but only among 1 percent of those under 50 years of age.
Such large-scale studies reveal clonal hematopoiesis with somatic mutations is not restricted to myelodysplastic syndromes. As a result, the term clonal hematopoiesis of indeterminate potential (CHIP) has been proposed to describe the presence of these mutations among individuals with no hematologic malignancy. Not only is CHIP a strong risk factor for hematologic cancer, but it has more recently also been associated with an increased risk of cardiovascular disease.
Implications for cardiovascular disease
Numerous studies have demonstrated a link between CHIP and cardiovascular disease. One study found that the presence of CHIP (detected by whole-exome sequencing) in peripheral blood cells is associated with nearly a doubling in the risk of coronary heart disease. In this same study, mutations in CHIP-associated genes DNMT3A, TET2, ASXL1, and JAK2 were also each individually associated with coronary heart disease. Moreover, carriers also exhibited increased coronary artery calcification. Further, disruption of Tet2 in atherosclerosis-prone mice resulted in elevated expression of inflammatory chemokine and cytokine genes, indicative of inflammation as a disease mechanism.
Indeed, based on these and other findings, inflammation is thought to be the key mechanism underlying CHIP-associated cardiovascular disease. CHIP-associated mutations also increase atherothrombotic risk via DNA methylation and stimulation of inflammatory chemokine and cytokine transcription and increased neutrophil extracellular trap formation.
Several different strategies to target high-risk CHIP mutations have been proposed. Various antibodies targeting inflammatory cytokines, JAK2 inhibitors, and the glucose-lowering drug metformin have been examined as potential interventions in the pre-clinical setting. Whether these strategies will translate into the clinical realm remains to be determined, and would necessitate increased CHIP screening and monitoring followed by clinical trials.
NGS for screening and detection
Currently, there is no consensus regarding which patients should be evaluated for CHIP. It is most often identified with NGS of blood or bone marrow for the purpose of evaluating other hematologic disorders, premature cardiovascular events, or to screen potential donors for hematopoietic cell transplantation.
As CHIP increases the risk of developing hematologic cancers and cardiovascular disease, screening and surveillance via NGS might enable earlier intervention for improved outcomes. However, there are several barriers to widespread screening. It is not possible to screen for CHIP with routine clinical assessment, and high costs are a barrier to routine NGS testing. Despite efforts to lower costs and improve accessibility, NGS is still not standard practice in most clinical settings.
With respect to hematologic cancer risk, there are no evidence-based monitoring guidelines for individuals diagnosed with CHIP, although a physical examination and complete blood count are recommended every three to six months. For CHIP-associated cardiovascular disease risk, there is a lack of clinical evidence for risk-reduction strategies. Current recommendations are to monitor CHIP patients for cardiovascular disease progression and provide counseling to discuss the importance of lifestyle changes for modifying risk.
As a relatively recent discovery, the full implications of CHIP in hematology and cardiology remain to be elucidated. A growing body of research demonstrating the association between CHIP and an increased risk of hematologic cancer and cardiovascular disease supports further investigation into mechanisms, causality, and novel treatment strategies to improve clinical outcomes. By supporting earlier interventions for hematologic cancers and cardiovascular disease, CHIP screening via NGS may become valuable tool for oncologists and cardiologists alike.