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Ferrata Storti Foundation
Haematologica 2019 Volume 104(12):2410-2417
Acute Myeloid Leukemia
Clonal hematopoiesis and risk of acute myeloid leukemia
Andrew L. Young,1,2 R. Spencer Tong,1,2 Brenda M. Birmann3* and Todd E. Druley1,2*
1Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, Saint Louis, MO; 2Center for Genome Sciences and Systems Biology, Washington University School of Medicine, Saint Louis, MO and 3Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
*BMB and TED contributed equally to this work.
ABSTRACT
Nearly all adults harbor acute myeloid leukemia (AML)-related clonal hematopoietic mutations at a variant allele fraction (VAF) of ≥0.0001, yet relatively few develop hematologic malignancies. We conducted a nested analysis in the Nurses’ Health Study and Health Professionals Follow-Up Study blood subcohorts, with up to 22 years of fol- low up to investigate associations of clonal mutations of ≥0.0001 allele fre- quency with future risk of AML. We identified 35 cases with AML that had pre-diagnosis peripheral blood samples and matched two controls without history of cancer per case by sex, age, and ethnicity. We conducted blinded error-corrected sequencing on all study samples and assessed variant-asso- ciated risk using conditional logistic regression. We detected AML-associat- ed mutations in 97% of all participants (598 mutations, 5.8/person). Individuals with mutations ≥0.01 variant allele fraction had a significantly increased AML risk (OR 5.4, 95%CI: 1.8-16.6), as did individuals with high- er-frequency clones and those with DNMT3A R882H/C mutations. The risk of lower-frequency clones was less clear. In the 11 case-control sets with samples banked ten years apart, clonal mutations rarely expanded over time. Our findings are consistent with published evidence that detec- tion of clonal mutations ≥0.01 VAF identifies individuals at increased risk for AML. Further study of larger populations, mutations co-occurring with- in the same pre-leukemic clone and other risk factors (lifestyle, epigenetics, etc.), are still needed to fully elucidate the risk conferred by low-frequency clonal hematopoiesis in asymptomatic adults.
Introduction
Clonal hematopoiesis of indeterminate potential (CHIP) has been defined as somatic mutations in the peripheral blood at variant allele fractions (VAF) >0.02 in individuals without evidence of hematologic malignancy.1 The threshold of 0.02 VAF was arbitrarily derived, reflecting the technical limitations of the standard next generation sequencing (NGS) and not biological risk of leukemic transformation with lower frequency mutations. To date, there have been no systematic screening recommendations for identifying or surveilling CHIP in healthy individuals. Nonetheless, the presence of CHIP has been shown to increase the risk of develop- ing hematologic malignancy (in aggregate) by 0.5-1% per year,2,3 although the absolute risk of leukemic transformation in individuals with CHIP is very low. Recently, two studies demonstrated an increased risk of developing AML in indi- viduals with CHIP detected using targeted sequencing of peripheral blood samples collected several years prior to diagnosis.4,5
Independently, error-corrected sequencing (ECS) has enabled accurate interroga- tion of the hematologic somatic mutational profile at VAF ≥0.00016 and demon- strated that selection of pre-existing clones can lead to therapy-related leukemia.7 Our ECS-based study of blood samples collected approximately ten years apart
Correspondence:
TODD E. DRULEY
druley_t@wustl.edu
Received: January 18, 2019. Accepted: April 16, 2019. Pre-published: April 19, 2019.
doi:10.3324/haematol.2018.215269
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/12/2410
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