A look at the impact of clonal hematopoiesis on clinical prognosis

Clonal hematopoiesis, a phenomenon in which stem cells in the blood produce a genetically distinct population of cells, has been attracting attention in recent years because of its association not only with hematological cancers but also with an increased risk of cardiovascular diseases. Clonal hematopoiesis had previously been reported to be caused by two types of genomic abnormalities: genetic mutations and copy number alterations (CNAs). However, the relationship between these genomic abnormalities was not clearly known owing to the lack of studies examining them simultaneously.

A research team led by Professor Seishi Ogawa and a doctoral student Ryunosuke Saiki of the Graduate School of Medicine at Kyoto University, Team Leader Yukihide Momozawa of the RIKEN Center for Integrative Medical Sciences, Professor Yoshinori Murakami of the Institute of Medical Science at the University of Tokyo, and Director Satoru Miyano of the M&D Data Science Center at the Tokyo Medical and Dental University conducted an integrated analysis of clonal hematopoiesis on approximately 10,000 subjects enrolled in the BioBank Japan (BBJ). The study revealed that genetic mutations and CNAs frequently coexist in clonal hematopoiesis, which significantly increases the risk of hematological malignancies and cardiovascular diseases. Professor Ogawa says, "It has recently been found that clonal hematopoiesis is found as frequently as hypertension. Nearly 40% of people over the age of 60 have clonal hematopoiesis, and those with clonal hematopoiesis were found to have a 1.3 times higher risk of cardiovascular diseases than healthy people, which is comparable to hypertension and diabetes. The appropriate intervention will be possible if genetic mutations and CNAs can be examined in a health checkup in the future." These findings were published in Nature Medicine.

In this study, the research team conducted an integrated analysis of genetic mutations and CNAs using peripheral blood samples from 11,234 subjects enrolled in BBJ. At least one of the abnormalities was detected in 40% of the subjects. In addition to this, 7% of the subjects (16% of positive cases) had both abnormalities. This indicated a statistically significant coexistence of the abnormalities, which suggested a coordinated relationship between the two. In particular, genetic mutations and CNAs frequently coexisted in some genes, including DNMT3A, TET2, JAK2, and TP53, likely resulting in their biallelic alterations. Although biallelic alterations of these genes have been noted in hematological cancers, this study revealed that they exist from the stage of clonal hematopoiesis.

Consistent with previous reports, the risk of hematological cancers was significantly high in patients with genetic mutations or CNAs, but among hematological cancers, the risk was higher in myeloid tumors than in lymphoid tumors. In addition, mortality from hematological cancers was higher in patients with both genetic mutations and CNAs than in those with a single abnormality, suggesting that both abnormalities are involved in the development of hematological cancers in a coordinated manner.

In particular, it was found that the risk is further increased when both abnormalities target the same gene (such as DNMT3A, TET2, TP53, and JAK2), resulting in biallelic alterations.

For cardiovascular diseases, the risk was significantly higher in patients with genetic mutations, as reported previously. Hypertension was frequently observed in patients with genetic mutations, further supporting the accepted notion that clonal hematopoiesis promotes arteriosclerosis. In addition, mortality from cardiovascular diseases was higher in patients with both genetic mutations and CNAs than in those with a single abnormality, and it was speculated that the two types of abnormalities act in a coordinated manner on the development of cardiovascular diseases.

These results indicate that genetic mutations and CNAs act in a coordinated manner on the risk of hematological cancers and cardiovascular diseases, and it is important to evaluate both in an integrated manner to gain an accurate understanding of the full impact of clonal hematopoiesis.

The results of this study not only provide clues to understand the origin of hematological cancers but are also expected to be important indicators for realizing the prediction of clinical prognosis based on clonal hematopoiesis.