Chipping Away at the Mystery of Clonal Hematopoiesis of Indeterminate Potential (CHIP)

Clinicians and researchers are working to uncover the prognostic value and health implications of clonal hematopoiesis of indeterminate potential (CHIP), a newly recognized condition characterized by the presence of somatic mutations in blood or bone marrow cells, most commonly on the DNMT3A gene. To date, CHIP mutations have been identified as a risk factor for the development of hematologic neoplasms and cardiovascular disease.

By definition, CHIP is present in otherwise healthy individuals and can be detected by deep sequencing of blood leukocytes. The incidence increases with age, and up to 10 percent of individuals in the eighth decade may harbor CHIP. The estimated rate of transformation of CHIP mutations to a hematological neoplasia may be as high as 0.5 to 1 percent per year, but precise data is not available.

Jaroslaw Maciejewski, MD, PhD, Chair of Cleveland Clinic Cancer Center’s Department of Translational Hematology and Oncology Research, discusses the prognostic relevance of CHIP mutations, the need for closer monitoring of patients who harbor them and current plans to establish Cleveland Clinic’s first CHIP clinic.

What is the relevance of CHIP mutations in the development of disease and, specifically, myelodysplastic syndromes (MDS)?

Dr. Maciejewski: Newer studies have shown that many otherwise healthy, mostly elderly individuals acquire mutations in their blood cells, indicative of the presence of mutant bone marrow stem cells. Normally, such mutations have been found in leukemia or MDS, so it came as a great surprise when they were discovered in otherwise healthy individuals. Subsequent studies have shown that some of these mutations may correspond to the early stages of the transformation process to MDS in some, but not all patients. Certain CHIP mutations have been associated with increased cardiovascular risk.

Why is there an increased interest in studying the association between CHIP mutations and disease?

Dr. Maciejewski: It seems that the presence of CHIP mutations may indicate an increased risk for the development of diseases later. The study of CHIP may allow us to better understand this risk and also determine the need for monitoring and possible preventive measures. With the increasing human life span, there will be more CHIP carriers and, the older we get, the chances that CHIP-related disorders will develop increases.

How prevalent are CHIP mutations in the general population?

Dr. Maciejewski: Approximately 1 in 20 individuals carries CHIP mutations at the age of 65, but we suspect that this number may be much higher in older people.

How are patients typically diagnosed with CHIP mutations?

Dr. Maciejewski: CHIP mutations are often diagnosed inadvertently during work up for other medical conditions such as malignancies. However, certain medical institutions are now considering screening for CHIP mutations as a general risk assessment in older individuals. Studies are now being conducted to find out whether the treatment of cancer can lead to the acquisition of CHIP or acceleration of CHIP evolution.

What are the main goals of the CHIP clinic?

Dr. Maciejewski: The presence of CHIP mutations begs multiple questions. Should we screen all people for CHIP mutations? What preventive measures can be undertaken to prevent the development of disease? Should CHIP screening and prevention be a systematic effort in older individuals or only in those groups considered to be at higher risk such as cancer treatment survivors? How do we counsel patients about the implications associated with carrying CHIP mutations?

In the scope of the CHIP clinic, multiple specialists will work on answering these questions and developing a preventative care and management plan for individuals carrying CHIP mutations. Furthermore, an additional goal is to educate the patients about the limitations of the prognostic value of CHIP mutations and address any issues they might encounter after being diagnosed.

How far in the process of establishing the clinic are you?

Dr. Maciejewski: Together with my colleagues, Hetty Carraway, MD, and Bhumika Patel, MD, we are working on formalizing the concept and developing a format for the clinic. In the long term, I envision that the cardiology and molecular pathology departments will join in as partners.

What would be the direct benefits for patients being seen in a CHIP clinic?

Dr. Maciejewski: Healthcare is evolving, and there is an increasing shift towards preventive care. For CHIP carriers with increased cardiovascular risk for example, we would offer more intense monitoring and advise patients on how to mitigate modifiable risk factors of cardiovascular disease, such as blood pressure and cholesterol levels. As our understanding of the effects of CHIP mutations on personalized risk of leukemia and MDS evolves, we envision that we will be able to offer additional specialty services, including monitoring or possibly prevention. CHIP clinics already exist at certain major medical institutions in the country and we plan on collaborating and learning from their experience to develop a model that is in line with our patients’ needs and Cleveland Clinic culture.

Image: Centrifugation of DNA samples prior to high-throughput genotyping and sequencing at the Cancer Genomics Research Laboratory, part of the National Cancer Institute’s Division of Cancer Epidemiology and Genetics (DCEG). Source: NCI Visuals Online. Photographer: Daniel Sone.