Epidemiology and Genetics of Clonal Hematopoiesis: A Premalignant Stem Cell Disorder

Reykjavik, Iceland, November 7, 2023 /PR Newswire/ --Amgen Subsidiary deCODE genetics Publishes Comprehensive New Study in Nature Genetics, Providing In-Depth Insights into the Epidemiology, Somatic and Germline Genetics of Clonal Hematopoiesis. Utilizing whole-genome sequence data from Iceland and the UK Biobank, combined with a unique somatic mutation barcoding strategy, the study conducts large-scale population research on clonal hematopoietic system disorders.

"Epidemiology and Genetics of Clonal Hematopoiesis – Premalignant Hematopoietic Stem Cell Disorders" The first author, a deCODE genetics scientistSimon N. StaceyHad a conversation with Kari Stefánsson, CEO of deCODE genetics.

Clonal Hematopoiesis: Insights into Genetics and Smoking-Related RisksClonal hematopoiesis refers to a condition that arises when a clone lineage of hematopoietic stem cells (HSCs) expands and becomes the source of most mature blood cells. Scientists at deCODE genetics utilized whole-genome sequence data from 176,000 individuals to detect clonal hematopoiesis in over 16,000 subjects. The study reaffirmed the high prevalence of clonal hematopoiesis abnormalities in the elderly (nearly 50% in those over 80 years old). Patients with clonal hematopoiesis are at a higher risk of being subsequently diagnosed with hematologic malignancies and also exhibit increased mortality. Clonal hematopoiesis was previously thought to be associated with various non-hematologic diseases, including cancer and cardiovascular disease. However, the research suggests that smoking behavior may accelerate the progression of clonal hematopoiesis in a dose-dependent manner and could be correlated with all related non-hematologic diseases. The study uncovered evidence of mutations in HSCs that drive their colony proliferation. Additionally, researchers identified 25 genetic sequence variants that make individuals more susceptible to clonal hematopoiesis. Scientists at deCODE developed a method to detect clonal hematopoiesis based on whole-genome sequencing. This method is grounded in the fact that each clone carries a unique "mutation barcode," which arises during development and is present in the founder cell at the onset of clonal expansion. If a specific HSC clone proliferates sufficiently, these mutation barcodes can be detected through sequencing, providing an indication of clonal hematopoiesis in patients. Clonal hematopoiesis exhibits many characteristics of pre-cancerous cell clone proliferation and poses a potential risk for malignant transformation. In fact, individuals with clonal hematopoiesis face a higher risk of developing hematologic malignancies and premature death. Surprisingly, while some of the increased mortality is due to hematologic malignancies, much of it can be attributed to smoking-related diseases. Clonal hematopoiesis not only increases the risk of hematologic malignancies but also shows clear associations with chronic obstructive pulmonary disease, lung cancer, peripheral artery disease, emphysema, and alcoholism. However, this study did not find evidence supporting the widely accepted link between clonal hematopoiesis and cardiovascular disease. The study found that smoking has a dose-dependent effect on clonal hematopoiesis and may accelerate its progression with age. This suggests that clonal hematopoiesis, in some aspects, serves as a marker of smoking rather than a correlation with non-hematologic diseases, which is essentially caused by smoking behavior and advanced age. Next, the genetic basis of clonal hematopoiesis was investigated in this study. The research first focused on possible mutations in HSCs, which give certain clone cells a selective advantage, enabling them to replace normal bone marrow and hematopoietic functions. Researchers identified several so-called driver mutations, many of which are associated with known myeloid and lymphoid neoplasms. However, most HSC clones do not have obvious driver mutations, and the reasons for their proliferation remain unknown. Regarding genetic variations predisposing individuals to clonal hematopoiesis (CH), deCODE identified 25 loci with relevant mutations. In some cases, these mutations were shown to affect gene expression, splicing, or plasma protein levels associated with CH. These mutations also often influence blood cell counts, myeloproliferative neoplasms, and leukocyte telomere length. In summary, this study provides substantial insights into the genetics and epidemiology of clonal hematopoiesis.

deCODE genetics, located in Reykjavik, Iceland, is a global leader in analyzing and understanding the human genome. deCODE has discovered genetic risk factors for dozens of common diseases using its unique expertise and population resources. The goal of understanding disease genetics is to use this information to create entirely new methods for diagnosing, treating, and preventing diseases. deCODE is a wholly-owned subsidiary of Amgen (NASDAQ: AMGN).