Somatic Mutations Predict Acute Myeloid Leukemia Years Before Diagnosis

Abstract

BackgroundSomatic mutations observed in clonal hematopoiesis are associated with increased age and risk of hematological malignancies. However, the limited number of acute myeloid leukemia (AML) patients in studies of clonal hematopoiesis thus far has precluded determination of the spectrum of mutations leading to AML and their impact on risk and time to diagnosis.\n\nMethodsThe relationship between baseline mutations and subsequent AML was determined in a case-control study design. 212 women eventually diagnosed with AML (median time: 9.8 years) were identified from the Womens Health Initiative cohort alongside 212 matched AML-free controls. Deep sequencing of 67 genes was performed on DNA isolated from peripheral blood to detect subclonal mutations.\n\nResultsThe presence of any mutation was associated with increased odds of eventual AML (odds ratio [OR] 4.0; 95% confidence interval [CI], 2.5-6.3). These odds were further elevated with mutations in IDH1/2 (OR 8.4; 95% CI, 1.4-51.9), TP53 (OR 54.2; 95% CI, 2.9-1017.7), or spliceosome genes (OR 5.6; 95% CI, 1.5-20.6). Eventual AML diagnosis occurred in all or most participants with mutations in TP53 (N=23/23) or IDH1/2 (N=15/16). Mutations indicated sooner AML diagnosis (median 8.0 vs. 11.9 years; P < 0.001) with TP53 mutations demonstrating increased odds of AML within 5 years (OR 3.6; 95% CI, 1.4-9.1).\n\nConclusionsMutations are present in peripheral blood of AML patients a decade prior to AML diagnosis with mutations in TP53 producing especially rapid presentation. Strategies for monitoring of high-risk populations are needed and clinical trials of potential early interventions can be considered.