Combined landscape of single-nucleotide variants and copy number alterations in clonal hematopoiesis

• Published in: Nature medicine Vol. 27; no. 7; pp. 1239 - 1249
• Main Authors: Saiki, Ryunosuke, Momozawa, Yukihide, Nannya, Yasuhito, Nakagawa, Masahiro M., Ochi, Yotaro, Yoshizato, Tetsuichi, Terao, Chikashi, Kuroda, Yutaka, Shiraishi, Yuichi, Chiba, Kenichi, Tanaka, Hiroko, Niida, Atsushi, Imoto, Seiya, Matsuda, Koichi, Morisaki, Takayuki, Murakami, Yoshinori, Kamatani, Yoichiro, Matsuda, Shuichi, Kubo, Michiaki, Miyano, Satoru, Makishima, Hideki, Ogawa, Seishi
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2021; Nature Publishing Group
• Subjects: 631/208; 631/67; 631/67/1990; 631/67/68; 631/67/69; Abnormalities; Aged; Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Blood; Cancer; Cancer Research; Cardiovascular disease; Cardiovascular diseases; Cardiovascular Diseases - genetics; Cardiovascular Diseases - mortality; Cardiovascular Diseases - pathology; Clonal Hematopoiesis - genetics; Copy number; Copy number variations; Deoxyribonucleic acid; Development and progression; Dioxygenases; DNA; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA Copy Number Variations - genetics; DNA Methyltransferase 3A; DNA sequencing; DNA-Binding Proteins - genetics; Female; Genes; Genetic aspects; Genetic Markers - genetics; Health risks; Hematologic Neoplasms - genetics; Hematologic Neoplasms - mortality; Hematologic Neoplasms - pathology; Hematology; Hematopoiesis; Hematopoietic Stem Cells - cytology; High-Throughput Nucleotide Sequencing; Humans; INDEL Mutation - genetics; Infectious Diseases; Janus kinase 2; Janus Kinase 2 - genetics; Male; Malignancy; Medical research; Medicine, Experimental; Metabolic Diseases; Middle Aged; Molecular Medicine; Mortality; Myeloproliferative disorders; Neurosciences; Nucleotides; p53 Protein; Phenotypes; Polymorphism, Single Nucleotide - genetics; Proto-Oncogene Proteins - genetics; Risk factors; Single nucleotide polymorphisms; Statistical analysis; Tumor Suppressor Protein p53 - genetics; Japan
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-021-01411-9

Clonal hematopoiesis (CH) in apparently healthy individuals is implicated in the development of hematological malignancies (HM) and cardiovascular diseases. Previous studies of CH analyzed either single-nucleotide variants and indels (SNVs/indels) or copy number alterations (CNAs), but not both. Here, using a combination of targeted sequencing of 23 CH-related genes and array-based CNA detection of blood-derived DNA, we have delineated the landscape of CH-related SNVs/indels and CNAs in 11,234 individuals without HM from the BioBank Japan cohort, including 672 individuals with subsequent HM development, and studied the effects of these somatic alterations on mortality from HM and cardiovascular disease, as well as on hematological and cardiovascular phenotypes. The total number of both types of CH-related lesions and their clone size positively correlated with blood count abnormalities and mortality from HM. CH-related SNVs/indels and CNAs exhibited statistically significant co-occurrence in the same individuals. In particular, co-occurrence of SNVs/indels and CNAs affecting DNMT3A , TET2 , JAK2 and TP53 resulted in biallelic alterations of these genes and was associated with higher HM mortality. Co-occurrence of SNVs/indels and CNAs also modulated risks for cardiovascular mortality. These findings highlight the importance of detecting both SNVs/indels and CNAs in the evaluation of CH. Analysis of single-nucleotide variants and copy number alterations gives a more complete picture of clonal hematopoiesis and its impact on hematological malignancy and cardiovascular disease.