CHIP highly relevant to individual risk profile for individuals aged ≥80 years
Clonal genetic changes in hematopoietic cells occur with increasing frequency with advancing age, even in individuals without hematological neoplasia. Due to the growing number of individuals aged ≥80 years in our society, the need arises to investigate the clinical relevance of such clonal hematopoiesis of indeterminate potential (CHIP). The focus here is on the relationship between CHIP and the development of myeloid neoplasia or cardiovascular disease for an individual risk assessment and potential early therapeutic intervention.
Frequency of CHIP and Effect on Survival in Individuals Aged ≥80 Years
- CHIP in approx. 30% of individuals
- The older the individual, the more frequent the occurrence of CHIP
CHIP more common in individuals with (non-hematological) chronic
- Lower probability of survival for individuals with CHIP, particularly
with ≥2 mutations
Approximately 30% of individuals were found to have at least one mutation in one of the genes studied, with the DNMT3A, TET2, and ASXL1 genes most frequently affected. The older the individual, the more frequently CHIP mutations were detected. Furthermore, CHIP mutations were approximately three times as common in individuals with non-hematological chronic diseases. In addition, individuals with CHIP had a lower probability of survival, whereby persons with ≥2 mutations exhibited an even less favorable prognosis (observation period of up to 15 years).
Influence of CHIP on Risk of Myeloid Neoplasms
- Absence of CHIP: high negative prediction value
- Number, type, and clone size of mutations as predictive markers for myeloid neoplasms
- Definition of 3 risk groups by mutation status and erythrocyte indices
- High prognostic relevance of mutations for cytopenia of undetermined significance
Rossi and colleagues demonstrated that CHIP mutations influenced the risk of developing a myeloid neoplasm in the cohort studied. The absence of CHIP turned out to be a strong negative predictor. A higher number of mutations as well as mutations in splicing genes (SF3B1, SRSF2, U2AF1, ZRSR2), JAK2 mutations, and DNMT3A, TET2, and ASXL1 mutations with mutations in additional genes were found to have a strong positive predictive value for the development of myeloid neoplasms. The risk of a myeloid neoplasm also increased when the allele frequency of the mutation was ≥9.6%. Using a risk score based on mutation status, mean red cell volume (MCV >98 fL), and red cell distribution width (RDW >14%), three risk groups for the occurrence of a myeloid neoplasm were defined. The combination of a cytopenia of undetermined significance with specific mutations (clonal cytopenia of unclear significance, CCUS) gave rise to a particularly unfavorable prognosis. Overall survival of individuals with this constellation did not differ from patients with a diagnosed myeloid neoplasm.
CHIP and Chronic Inflammatory Disease or Coronary Heart Disease in Individuals Aged ≥80 Years
The risk of coronary heart disease was also higher in individuals with CHIP mutations. DNMT3A, TET2, ASXL1, or JAK2 mutations turned out to be high-risk mutations which, in addition, also indicated an increased risk of rheumatoid arthritis.
The study by Rossi and colleagues demonstrates the significance of CHIP for individual risk assessment and prognosis, particularly in older individuals. A mutation analysis may be particularly useful for further classification of an unexplained cytopenia. Based on research findings such as these, we are constantly considering adjustments and additions to our diagnostic services in order to identify potential risk factors at an early stage.