Elisabeth A Goldman, Paul T Spellman, Anupriya Agarwal
{"title":"定义具有不确定潜能的克隆造血:衰老和炎症下的进化动态和检测。","authors":"Elisabeth A Goldman, Paul T Spellman, Anupriya Agarwal","doi":"10.1101/mcs.a006251","DOIUrl":null,"url":null,"abstract":"<p><p>Clonal hematopoiesis (CH), in which hematopoietic stem and progenitor cell (HSPC) clones and their progeny expand in the circulating blood cell population, occurs following the acquisition of somatic driver mutations. Individuals diagnosed with clonal hematopoiesis of indeterminate potential (CHIP) carry somatic mutations in hematological malignancy-associated driver genes, historically at or above a variant allele frequency of 2%, but do not exhibit abnormal blood cell counts or any other symptoms of hematologic disease. However, CHIP is associated with moderately increased risk of hematological cancer and a greater likelihood of cardiovascular and pulmonary disease. Recent advances in the resolution of high-throughput sequencing experiments suggest CHIP is much more prevalent in the population than once thought, particularly among those aged 60 and over. Although CHIP does elevate the risk of eventual hematological malignancy, only one in 10 individuals with CHIP will receive such a diagnosis; the problem lies in the continued difficulty in accurately separating the 10% of CHIP patients who are most likely to be in a premalignant state from those who are not, given the heterogeneity of this condition and the etiology of the associated hematological cancers. Concerns over the risk of eventual malignancies must be balanced with growing recognition of CH as a common age-dependent occurrence, and efforts to better characterize and differentiate oncogenic clonal expansion from that which is much more benign. In this review, we discuss evolutionary dynamics of CH and CHIP, the relationship of CH to aging and inflammation, and the role of the epigenome in promoting potentially pathogenic or benign cellular trajectories. We outline molecular mechanisms that may contribute to heterogeneity in the etiology of CHIP and the incidence of malignant disease among individuals. Finally, we discuss epigenetic markers and modifications for CHIP detection and monitoring with the potential for translational applications and clinical utility in the near future.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":null,"pages":null},"PeriodicalIF":1.8000,"publicationDate":"2023-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c5/b1/MCS006251Gol.PMC10240836.pdf","citationCount":"0","resultStr":"{\"title\":\"Defining clonal hematopoiesis of indeterminate potential: evolutionary dynamics and detection under aging and inflammation.\",\"authors\":\"Elisabeth A Goldman, Paul T Spellman, Anupriya Agarwal\",\"doi\":\"10.1101/mcs.a006251\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Clonal hematopoiesis (CH), in which hematopoietic stem and progenitor cell (HSPC) clones and their progeny expand in the circulating blood cell population, occurs following the acquisition of somatic driver mutations. Individuals diagnosed with clonal hematopoiesis of indeterminate potential (CHIP) carry somatic mutations in hematological malignancy-associated driver genes, historically at or above a variant allele frequency of 2%, but do not exhibit abnormal blood cell counts or any other symptoms of hematologic disease. However, CHIP is associated with moderately increased risk of hematological cancer and a greater likelihood of cardiovascular and pulmonary disease. Recent advances in the resolution of high-throughput sequencing experiments suggest CHIP is much more prevalent in the population than once thought, particularly among those aged 60 and over. Although CHIP does elevate the risk of eventual hematological malignancy, only one in 10 individuals with CHIP will receive such a diagnosis; the problem lies in the continued difficulty in accurately separating the 10% of CHIP patients who are most likely to be in a premalignant state from those who are not, given the heterogeneity of this condition and the etiology of the associated hematological cancers. Concerns over the risk of eventual malignancies must be balanced with growing recognition of CH as a common age-dependent occurrence, and efforts to better characterize and differentiate oncogenic clonal expansion from that which is much more benign. In this review, we discuss evolutionary dynamics of CH and CHIP, the relationship of CH to aging and inflammation, and the role of the epigenome in promoting potentially pathogenic or benign cellular trajectories. We outline molecular mechanisms that may contribute to heterogeneity in the etiology of CHIP and the incidence of malignant disease among individuals. Finally, we discuss epigenetic markers and modifications for CHIP detection and monitoring with the potential for translational applications and clinical utility in the near future.</p>\",\"PeriodicalId\":10360,\"journal\":{\"name\":\"Cold Spring Harbor Molecular Case Studies\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.8000,\"publicationDate\":\"2023-05-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c5/b1/MCS006251Gol.PMC10240836.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cold Spring Harbor Molecular Case Studies\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/mcs.a006251\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/4/1 0:00:00\",\"PubModel\":\"Print\",\"JCR\":\"Q3\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cold Spring Harbor Molecular Case Studies","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/mcs.a006251","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/4/1 0:00:00","PubModel":"Print","JCR":"Q3","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Defining clonal hematopoiesis of indeterminate potential: evolutionary dynamics and detection under aging and inflammation.
Clonal hematopoiesis (CH), in which hematopoietic stem and progenitor cell (HSPC) clones and their progeny expand in the circulating blood cell population, occurs following the acquisition of somatic driver mutations. Individuals diagnosed with clonal hematopoiesis of indeterminate potential (CHIP) carry somatic mutations in hematological malignancy-associated driver genes, historically at or above a variant allele frequency of 2%, but do not exhibit abnormal blood cell counts or any other symptoms of hematologic disease. However, CHIP is associated with moderately increased risk of hematological cancer and a greater likelihood of cardiovascular and pulmonary disease. Recent advances in the resolution of high-throughput sequencing experiments suggest CHIP is much more prevalent in the population than once thought, particularly among those aged 60 and over. Although CHIP does elevate the risk of eventual hematological malignancy, only one in 10 individuals with CHIP will receive such a diagnosis; the problem lies in the continued difficulty in accurately separating the 10% of CHIP patients who are most likely to be in a premalignant state from those who are not, given the heterogeneity of this condition and the etiology of the associated hematological cancers. Concerns over the risk of eventual malignancies must be balanced with growing recognition of CH as a common age-dependent occurrence, and efforts to better characterize and differentiate oncogenic clonal expansion from that which is much more benign. In this review, we discuss evolutionary dynamics of CH and CHIP, the relationship of CH to aging and inflammation, and the role of the epigenome in promoting potentially pathogenic or benign cellular trajectories. We outline molecular mechanisms that may contribute to heterogeneity in the etiology of CHIP and the incidence of malignant disease among individuals. Finally, we discuss epigenetic markers and modifications for CHIP detection and monitoring with the potential for translational applications and clinical utility in the near future.
期刊介绍:
Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.