Insights into clonal hematopoiesis and its relation to cancer risk

Abstract

In the multi-hit model of carcinogenesis, a precancerous state often precedes overt malignancy. Identification of these states has been of great interest as they allow for early identification of at-risk individuals before the appearance of a future cancer. One such condition has recently been described for blood cancers: Clonal Hematopoiesis of Indeterminate Potential (CHIP). Recent research advances have elucidated the risk of progression of CHIP to myeloid malignancies, its potential as a precursor for non-myeloid blood cancers, and its association with non-hematological cancers. Understanding the evolution of CHIP to hematological malignancy may help identify CHIP carriers at high risk of transformation and lead to the development of targeted therapies that can be deployed preemptively.

Figure 1. Aging increases risk for clonal hematopoiesis and hematological malignancies.

A) Representation of CH driver mutations as a function of aging. After clonal expansion, CH clones may acquire additional secondary mutations that induce malignant transformation. B) Prevalence of CHIP and AML as a function of age. Data for the prevalence of CHIP were adopted from studies found in Jaiswal et al. 2014 [9]. Prevalence of AML among patients in the US were reported using Surveillance Research Program, National Cancer Institute SEER*Explorer (seer.cancer.gov/explorer) for AML patients diagnosed between 2013–2017 [57].

Figure 2. Risk factors for progression of CHIP to malignancies.

CHIP is derived from clonal hematopoiesis (CH) once clonal mutated cells carry a VAF of at least 2% and harbor at least one mutation commonly found in hematological malignancies. CHIP may progress to clonal cytopenia, MDS, or AML in some people. Several features distinguish non-malignant carriers of CHIP from those at high-risk of transformation. Those who progress to MDS or AML are more likely to have larger VAFs in comparison to control groups. Patients who go on to develop malignancy also typically harbor a different mutational profile and carry multiple driver mutations in comparison to those who are non-malignant carriers.