3 years ago

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

Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes
David B. Solit, Maria E. Arcila, Aijazuddin Syed, José Baselga, Martin S. Tallman, Philip Jonsson, David M. Hyman, Sean M. Devlin, Michael F. Berger, Marc Ladanyi, Ashwin Kishtagari, Ahmet Zehir, Ross L. Levine, Mark E. Robson, Catherine C. Coombs

Summary

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.

Publisher URL: http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(17)30289-8

DOI: 10.1016/j.stem.2017.07.010

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