Editors' ChoiceCancer

“CHIP”s are bad for patients with solid tumors

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Science Translational Medicine  23 Aug 2017:
Vol. 9, Issue 404, eaao4212
DOI: 10.1126/scitranslmed.aao4212

Abstract

In patients with nonhematologic cancers, clonal hematopoiesis is prevalent and associated with poor prognoses.

Aging in even healthy individuals is associated with acquisition of recurrent somatic mutations of leukemia-associated genes, including DNMT3A, TET2, and ASXL1, in hematopoietic stem cells (HSC). These mutations persist over time and lead to clonal expansion of HSCs, a condition referred to as clonal hematopoiesis (CH) or clonal hematopoiesis of indeterminate potential (CHIP). The incidence of CH increases with age and is associated with increased risk of developing a hematologic malignancy and decreased overall survival. In patients with nonhematologic cancers, the prevalence and clinical impact of CH is not well described.

Coombs et al. used a deep-coverage, targeted, next-generation sequencing assay on paired tumor and blood samples from almost 9000 patients with nonhematologic cancers to determine the prevalence of CH in this patient population. CH was identified in a quarter of patients with mutations in DNMT3A, TET2, PPM1D, ASXL1, ATM, and TP53 accounting for 60% of detected mutations. A subset of higher clonal burden CH mutations in leukemia-associated genes were identified as putative driver mutations (CH-PD) and occurred in 4.5% of patients. In this cohort, CH led to alterations in hematopoiesis and was associated with increasing age, tobacco use, and prior radiation therapy. In addition, specific prior exposures had an impact on the spectrum of mutations identified. CH and CH-PD both significantly increased the risk of developing a hematologic malignancy. Although both CH and CH-PD were associated with an inferior overall survival related to death from nonhematological cancer progression, only CH-PD remained significant after stratification for age, gender, and smoking status. Notably, the most significant negative impact on survival occurred in CH-PD with larger clonal burdens.

Development of CH, influenced by acquisition of mutations in aging HSCs and clonal selection by environmental and therapeutic exposures, negatively impacts survival related to nonhematologic malignancies and increases the risk of developing secondary hematologic malignancies. The finding that certain subsets of mutations and differences in clonal burden influenced these risks suggests that larger patient cohorts and longer patient follow-up are needed to further define clinically relevant CH and develop strategies, such as choice of initial anti-cancer therapies and lifestyle modifications to prevent CH and targeted therapies against CH, to mitigate risks of adverse outcome related to CH.

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