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Cell Stem Cell. 2017 Sep 7;21(3):374-382.e4. doi: 10.1016/j.stem.2017.07.010. Epub 2017 Aug 10.

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

Author information

1
Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Department of Medicine, Developmental Therapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA.
6
Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
7
Department of Medicine, Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Hereditary Cancer and Genetics Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA.
8
Department of Medicine, Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
9
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
10
Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA.
11
Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Memorial Sloan Kettering Cancer Center, Center for Hematologic Malignancies, New York, NY 10065, USA. Electronic address: leviner@mskcc.org.
12
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: bergerm1@mskcc.org.

Abstract

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.

KEYWORDS:

biological sciences; cancer; cancer genomics; diseases; genetics; health sciences; hematological cancer; hematological diseases; mutation

PMID:
28803919
PMCID:
PMC5591073
DOI:
10.1016/j.stem.2017.07.010
[Indexed for MEDLINE]
Free PMC Article

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