Somatic mutations precede acute myeloid leukemia years before diagnosis
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Abstract
The pattern of somatic mutations observed at diagnosis of acute myeloid leukemia (AML) has been well-characterized. However, the premalignant mutational landscape of AML and its impact on risk and time to diagnosis is unknown. Here we identified 212 women from the Women's Health Initiative who were healthy at study baseline, but eventually developed AML during follow-up (median time: 9.6 years). Deep sequencing was performed on peripheral blood DNA of these cases and compared to age-matched controls that did not develop AML. We discovered that mutations in IDH1, IDH2, TP53, DNMT3A, TET2 and spliceosome genes significantly increased the odds of developing AML. All subjects with TP53 mutations (n = 21 out of 21 patients) and IDH1 and IDH2 (n = 15 out of 15 patients) mutations eventually developed AML in our study. The presence of detectable mutations years before diagnosis suggests that there is a period of latency that precedes AML during which early detection, monitoring and interventional studies should be considered.
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Progression to hematological malignancies depends on the type and complexity of mutations in CHIP.
“Furthermore, progression to hematological malignancies depends on the type and complexity of mutations in CHIP.2,5,6”
From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [6]
The Discussion reports that mutation type, high allelic fractions, and clonal complexity are associated with higher risk of progression to AML; the baseline-mutations section also reports different AML risks for different mutated genes. The study addresses AML specifically, not hematological malignancies generally, and reports associations rather than establishing that progression depends on these features. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHigher TET2 mutant clone sizes associate with higher risk of progression to AML (VAF > 10%).
“Higher TET2 mutant clone sizes associate with higher risk of progression to AML (VAF > 10%)6”
From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [6]
Individuals with antecedent clonal hematopoiesis were at approximately 3 to 5-fold increased risk for developing AML in the subsequent years.
“Both groups found that individuals with antecedent clonal hematopoiesis were at ~3 to 5-fold increased risk for developing AML in the subsequent years (Fig. 3A).”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [72]
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- Authors
- Desai, P., Mencia-Trinchant, N., Savenkov, O., Simon, M. S., Cheang, G., Lee, S., Samuel, M., Ritchie, E. K., Guzman, M. L., Ballman, K. V., Roboz, G. J., & Hassane, D. C.
- Affiliations
- Weill Cornell Medicine (US)
- The Barbara Ann Karmanos Cancer Institute (US)
- Cornell University (US)
- Corresponding author
- Desai, Pinkal
- Hassane, Duane C.
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-07
- Volume
- 24
- Issue
- 7
- Pages
- 1015-1023
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6849383
- OpenAlex
- W2783064655
- Cited by
- 619
- References
- 39
- Citations by year
- 2026: 35 · 2025: 63 · 2024: 68 · 2023: 86 · 2022: 89 · 2021: 87 · 2020: 91 · 2019: 69 · 2018: 28
- FWCI
- 49.31
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health and Human Services (42129‐32, 42107-26, 32108‐9, 32118-32119, 32115, 32111‐13, P30-CA022453, 32100‐2, 44221, 32105‐6, 32122, 24152, N01-WH-2-2110)
- National Institutes of Health (32122, 32111‐13, 32108‐9, 42129‐32, 42107–26, n01wh22110-38-0-0, 32118-32119, 44221, 32115, 32100‐2, 24152, N01 WH022110, 32105-6)
- Weill Cornell Medical College
- National Heart, Lung, and Blood Institute (32100‐2, 32118‐32119, N01‐WH‐22110, 32118, 42107‐26, 32119, 24152, 32105–6, 32108‐9, 32111–13, 32115, 42129‐32, 32122, 44221)
- National Cancer Institute (32115, N01WH22110, NCI P30CA022453, P30CA022453)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- acute myeloid leukemia, somatic mutations, TP53 mutation, IDH1 mutation, IDH2 mutation, DNMT3A mutation, TET2 mutation, spliceosome mutations, cancer risk, time to diagnosis, leukemia latency, early detection, Women's Health Initiative
- MeSH terms
- Alleles, Female, Humans, Mutation, Risk Factors, Leukemia, Myeloid, Acute, Multivariate Analysis, Odds Ratio, Case-Control Studies, Disease Progression, Mutation Rate, Clonal Evolution
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