TY - JOUR
T1 - Clonal hematopoiesis and risk of acute myeloid leukemia
AU - Young, Andrew L.
AU - Spencer Tong, R.
AU - Birmann, Brenda M.
AU - Druley, Todd E.
N1 - Funding Information:
This project was supported in part by the National Institutes of Health (R01 CA211711, UM1 CA186107, P01 CA87969, R01 CA49449, UM1 CA167552 and R01 CA149445), the Children's Discovery Institute of Washington University and St Louis Children's Hospital (MC-II-2015-461), and Hyundai Hope on Wheels (2015Q3-3).
Publisher Copyright:
© 2019 Ferrata Storti Foundation. All rights reserved.
PY - 2019
Y1 - 2019
N2 - N early 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.
AB - N early 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.
UR - http://www.scopus.com/inward/record.url?scp=85066252400&partnerID=8YFLogxK
U2 - 10.3324/haematol.2018.215269
DO - 10.3324/haematol.2018.215269
M3 - Article
C2 - 31004019
AN - SCOPUS:85066252400
VL - 104
SP - 2410
EP - 2417
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 12
ER -