Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence
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- 6 days ago
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Author: Pratham Sarkar
Introduction
Clonal hematopoiesis, or Clonal Hematopoiesis of Indeterminate Potential (CHIP), is the expansion of clones of blood stem cells harboring somatic mutations, typically with no symptoms whatsoever. The condition becomes more prevalent with increasing age and has been associated with an increased risk of malignancies of the blood. A seminal 2014 publication in the New England Journal of Medicine by Genovese et al. demonstrated that clonal hematopoiesis is identifiable through DNA sequencing of blood specimens and is highly correlated with the subsequent development of hematologic cancers.
Methods
Whole-exome sequencing of blood samples from 12,380 individuals, predominantly over the age of 65, was performed in the NEJM study. DNA was extracted from granulocytes, and mutations were identified by analyzing the frequency of abnormal variants. Individuals
were followed for up to seven years using national health registries for the development of disease.
Prevalence and Genetic Results
Clonal hematopoiesis was uncommon in individuals below the age of 50 but was found in around 10% of individuals above the age of 65. DNMT3A, TET2, and ASXL1 were the genes most frequently mutated genes in blood cancers like leukemia. These types of mutations give a growth advantage to specific clones of blood cells, which then go on to proliferate over time.
Enhanced Cancer Risk
Individuals with clonal hematopoiesis were nearly 13 times more likely to be diagnosed with blood cancers than individuals with no detectable clones. In a majority of cases, the clones were visible months or even years before the individual was diagnosed with a cancer, suggesting that clonal hematopoiesis is an early step in the formation of cancer.
Health Risks Beyond Cancer
CHIP is not only linked to blood cancer. Other research has indicated that CHIP carriers also
have higher risks for cardiovascular disease, including heart attack and stroke. Inflammatory mechanisms seem to be at play, since mutations in genes like TET2 can lead to hyperactive immune function and inflammation.
Clinical Implications CHIP is now more and more defined as the occurrence of somatic mutations in blood cells with a VAF of 2% or higher, but in the absence of clinical presentation of any blood disorder. Although screening for CHIP is not yet routine, identification of CHIP through other genetic testing can trigger enhanced medical surveillance. Certain mutations, particularly in genes such as TP53 or IDH2, are high risk and need to be watched more closely.
Mechanisms and Future Directions The CHIP mutations preferentially affect genes that participate in DNA methylation and RNA splicing. The alterations enable the cells to escape normal regulatory constraints, resulting in clonal expansion. Scientists are investigating the role of inflammation in CHIP's health dangers and whether anti-inflammatory medications might mitigate the dangers. Treatments such as IL-1β inhibitors are being clinically evaluated in individuals with particular CHIP mutations. Furthermore, researchers are trying to additionally delineate the whole range of genes implicated in clonal hematopoiesis and create risk scores that might inform patient management. With the decreasing cost of sequencing technology and its increasing availability, CHIP detection will soon be routine in the practice of individualized medicine.
Conclusion: Clonal hematopoiesis is a common aging phenomenon that increases not only the risk of blood cancer but also other illnesses like heart disease. The discovery that the sequencing of straightforward blood DNA identifies individuals at risk years in advance has transformed our understanding of the initiation of cancer and the hazards of aging on health. Additional research will continue to uncover methods of how to optimally monitor and treat individuals with CHIP to improve long-term outcomes.
Works Cited
Genovese, Giulio, et al. “Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence.” New England Journal of Medicine, vol. 371, no. 26, 25 Dec. 2014, pp. 2477–2487, https://doi.org/10.1056/nejmoa1409405.
Pich, Oriol, et al. “Discovering the Drivers of Clonal Hematopoiesis.” Nature Communications, vol. 13, 23 July 2022, p. 4267, www.ncbi.nlm.nih.gov/pmc/articles/PMC9308779/, https://doi.org/10.1038/s41467-022-31878-0. Accessed 28 Sept. 2022.
Walsh, Kenneth. “The Emergence of Clonal Hematopoiesis as a Disease Determinant.” Journal of Clinical Investigation, vol. 134, no. 19, 30 Sept. 2024, www.jci.org/articles/view/180063?utm_source=chatgpt.com, https://doi.org/10.1172/jci180063. Accessed 25 June 2025.
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