Defining clonal hematopoiesis of indeterminate potential: evolutionary dynamics and detection under aging and inflammation.

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Cold Spring Harbor Molecular Case Studies Pub Date : 2023-05-09 Print Date: 2023-04-01 DOI:10.1101/mcs.a006251
Elisabeth A Goldman, Paul T Spellman, Anupriya Agarwal
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引用次数: 0

Abstract

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.

Abstract Image

Abstract Image

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。
克隆性造血(CH)是指造血干细胞和祖细胞(HSPC)克隆及其后代在循环血细胞群中扩增,是在获得体细胞驱动基因突变后发生的。被诊断为不确定潜能克隆性造血(CHIP)的患者携带血液恶性肿瘤相关驱动基因的体细胞突变,其变异等位基因频率历来达到或超过 2%,但不表现出血细胞计数异常或任何其他血液病症状。然而,CHIP 会导致罹患血液肿瘤的风险中度增加,并增加罹患心血管和肺部疾病的可能性。高通量测序实验分辨率的最新进展表明,CHIP 在人群中的发病率远比人们想象的要高,尤其是在 60 岁及以上的人群中。虽然CHIP确实会增加最终罹患血液恶性肿瘤的风险,但每10个CHIP患者中只有1人会得到这样的诊断;问题在于,鉴于这种疾病的异质性和相关血液癌症的病因,要准确区分10%最有可能处于恶性前状态的CHIP患者和非恶性前状态的CHIP患者仍然存在困难。在关注最终恶性肿瘤风险的同时,我们必须认识到CH是一种常见的年龄依赖性疾病,并努力更好地描述和区分致癌克隆扩增与良性克隆扩增。在这篇综述中,我们将讨论 CH 和 CHIP 的进化动态、CH 与衰老和炎症的关系,以及表观基因组在促进潜在致病或良性细胞轨迹中的作用。我们概述了可能导致 CHIP 病因异质性和个体间恶性疾病发病率的分子机制。最后,我们讨论了用于 CHIP 检测和监控的表观遗传标记和修饰,这些标记和修饰在不久的将来有可能转化应用和用于临床。
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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
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.
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