SNVs/indels and CNAs occur individually and together in clonal hematopoiesis and can affect the same genes.

  • Major Finding: SNVs/indels and CNAs occur individually and together in clonal hematopoiesis and can affect the same genes.

  • Concept: Mortality from hematologic malignancies correlated with the total number of CH-related SNVs/indels and CNAs.

  • Impact: Analyzing both types of mutations provides new insights into clonal hematopoiesis and disease outcomes.

The expansion of specific clones within a phenotypically normal hematopoietic compartment, known as clonal hematopoiesis (CH), in apparently healthy people has been linked with an increased risk of cardiovascular diseases and the development of hematologic malignancies. CH has historically been investigated by analyzing either copy-number alterations (CNA) or single-nucleotide variants (SNV) and insertions/deletions (indels) in cancer patients, but both approaches have rarely been combined in large general populations. In this study, Saiki, Momozawa, and colleagues analyzed blood-derived DNA samples from 11,234 individuals, including 672 people who went on to develop a hematological malignancy, using targeted sequencing of 23 CH-associated genes and SNP array-based copy-number analysis. Among the individuals analyzed, 27.3% had at least one SNV/indel with a median variant allele frequency of 3.0%, and a correlation was observed between older age and presence of CH-related SNVs/indels. The most frequently mutated genes were DNMT3A, TET2, ASXL1, and PPM1D, with several combinations of mutations of these genes found in the same sample more regularly than predicted by chance. Overall, CNAs were found in 20.1% of cases, and 7% of the cohort had both SNVs/indels and CNAs. Of note, SNVs/indels and CNAs affecting DNMT3A, TET2, JAK2, and TP53 were associated with loss of heterozygosity at these loci in samples with CH, suggesting a potential role for biallelic alterations in CH and disease evolution. When all types of mutation were combined, CH was detected in 40% of people >60 years old with no cancer history and in 56% of individuals who developed a hematologic malignancy. People with more CH-associated mutations had a higher frequency of blood abnormalities, and the presence of CH also increased the risk of mortality from cardiovascular diseases together with the incidence of hypertension, independent of other known risk factors. This detailed analysis of CH in a large cohort of elderly individuals facilitated the estimation of CH-associated hematologic malignancy mortality and points to a combined effect of CNAs and SNVs/indels in CH.

Saiki R, Momozawa Y, Nannya Y, Nakagawa MM, Ochi Y, Yoshizato T, et al. Combined landscape of single-nucleotide variants and copy number alterations in clonal hematopoiesis. Nat Med 2021;27:1239–49.

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