Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes

Publication date: Available online 10 August 2017
Source:Cell Stem Cell
Author(s): Catherine C. Coombs, Ahmet Zehir, Sean M. Devlin, Ashwin Kishtagari, Aijazuddin Syed, Philip Jonsson, David M. Hyman, David B. Solit, Mark E. Robson, José Baselga, Maria E. Arcila, Marc Ladanyi, Martin S. Tallman, Ross L. Levine, Michael F. Berger
Clonal hematopoiesis (CH), as evidenced by recurrent somatic mutations in leukemia-associated genes, commonly occurs among aging human hematopoietic stem cells. We analyzed deep-coverage, targeted, next-generation sequencing (NGS) data of paired tumor and blood samples from 8,810 individuals to assess the frequency and clinical relevance of CH in patients with non-hematologic malignancies. We identified CH in 25% of cancer patients, with 4.5% harboring presumptive leukemia driver mutations (CH-PD). CH was associated with increased age, prior radiation therapy, and tobacco use. PPM1D and TP53 mutations were associated with prior exposure to chemotherapy. CH and CH-PD led to an increased incidence of subsequent hematologic cancers, and CH-PD was associated with shorter patient survival. These data suggest that CH occurs in an age-dependent manner and that specific perturbations can enhance fitness of clonal hematopoietic stem cells, which can impact outcome through progression to hematologic malignancies and through cell-non-autonomous effects on solid tumor biology.

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Teaser

Coombs et al. examined a large cohort of solid tumor patients who underwent deep-coverage, paired tumor/blood sequencing and demonstrated that clonal hematopoiesis is common and associated with increasing age, tobacco use, and prior radiation therapy and that it predicts an increased risk of hematologic cancers and shorter survival.


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