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Haematologica. 2019 Apr 19. pii: haematol.2018.215269. doi: 10.3324/haematol.2018.215269. [Epub ahead of print]

Clonal haematopoiesis and risk of acute myeloid leukemia.

Author information

1
Washington University School of Medicine in St. Louis.
2
Washington University School of Medicine.
3
Brigham and Women's Hospital and Harvard Medical School.
4
Washington University School of Medicine; druley_t@wustl.edu.

Abstract

Nearly all adults harbor acute myeloid leukemia-related clonal hematopoietic mutations at a variant allele fraction 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 follow-up, to investigate associations of clonal mutations of ≥0.0001 allele frequency with future risk of acute myeloid leukemia. We identified 35 cases with acute myeloid leukemia 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-associated risk using conditional logistic regression. We detected acute myeloid leukemia-associated mutations in 97% of all participants (598 mutations, 5.8/person). Individuals with mutations ≥0.01 variant allele fraction had a significantly increased acute myeloid leukemia risk (OR 5.4, 95% CI 1.8-16.6), as did individuals with higher-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 10 years apart, clonal mutations rarely expanded over time. Our findings are consistent with published evidence that detection of clonal mutations ≥0.01 variant allele fraction identifies individuals at increased risk for acute myeloid leukemia. Further study of larger populations, mutations co-occurring within 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.

KEYWORDS:

Acute Myeloid Leukemia; clonal hematopoiesis; computational biology; genomics

PMID:
31004019
DOI:
10.3324/haematol.2018.215269
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