Journal
HAEMATOLOGICA
Volume 104, Issue 12, Pages 2410-2417Publisher
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2018.215269
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Funding
- National Institutes of Health [R01 CA211711, UM1 CA186107, P01 CA87969, R01 CA49449, UM1 CA167552, R01 CA149445]
- Children's Discovery Institute of Washington University [MC-II-2015-461]
- St Louis Children's Hospital [MC-II-2015-461]
- Hyundai Hope on Wheels [2015Q3-3]
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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 follow up to investigate associations of clonal mutations of >= 0.0001 allele frequency 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-associated risk using conditional logistic regression. We detected AML-associated 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 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 ten years apart, clonal mutations rarely expanded over time. Our findings are consistent with published evidence that detection of clonal mutations >= 0.01 VAF identifies individuals at increased risk for AML. 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.
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