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Rare Event Detection Using Error-corrected DNA and RNA Sequencing
Published on: August 3, 2018
Persistent Molecular Disease in Adult Patients With AML Evaluated With Whole-Exome and Targeted Error-Corrected DNA
Michael J Slade1, Reza Ghasemi1, Michelle O'Laughlin2
1Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.
Purpose:
Persistent molecular disease (PMD) after induction chemotherapy predicts relapse in AML. In this study, we used whole-exome sequencing (WES) and targeted error-corrected sequencing to assess the frequency and mutational patterns of PMD in 30 patients with AML.
Materials And Methods:
The study cohort included 30 patients with adult AML younger than 65 years who were uniformly treated with standard induction chemotherapy. Tumor/normal WES was performed for all patients at presentation. PMD analysis was evaluated in bone marrow samples obtained during clinicopathologic remission using repeat WES and analysis of patient-specific mutations and error-corrected sequencing of 40 recurrently mutated AML genes (MyeloSeq).
Results:
WES for patient-specific mutations detected PMD in 63% of patients (19/30) using a minimum variant allele fraction (VAF) of 2.5%. In comparison, MyeloSeq identified persistent mutations above 0.1% VAF in 77% of patients (23/30). PMD was usually present at relatively high levels (>2.5% VAFs), such that WES and MyeloSeq agreed for 73% of patients despite differences in detection limits. Mutations in DNMT3A, ASXL1, and TET2 (ie, DTA mutations) were persistent in 16 of 17 patients, but WES also detected non-DTA mutations in 14 of these patients, which for some patients distinguished residual AML cells from clonal hematopoiesis. Surprisingly, MyeloSeq detected additional variants not identified at presentation in 73% of patients that were consistent with new clonal cell populations after chemotherapy.
Conclusion:
PMD and clonal hematopoiesis are both common in patients with AML in first remission. These findings demonstrate the importance of baseline testing for accurate interpretation of mutation-based tumor monitoring assays for patients with AML and highlight the need for clinical trials to determine whether these complex mutation patterns correlate with clinical outcomes in AML.
Insights
Persistent molecular disease (PMD) is common after AML chemotherapy. Targeted sequencing detected more PMD than whole-exome sequencing, revealing new mutations post-treatment.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Persistent molecular disease (PMD) after induction chemotherapy is a key predictor of relapse in acute myeloid leukemia (AML).
- Understanding the frequency and mutational patterns of PMD is crucial for monitoring treatment response and predicting patient outcomes.
Purpose of the Study:
- To assess the frequency and mutational patterns of persistent molecular disease (PMD) in patients with acute myeloid leukemia (AML) after induction chemotherapy.
- To compare the efficacy of whole-exome sequencing (WES) and targeted error-corrected sequencing (MyeloSeq) in detecting PMD.
Main Methods:
- Whole-exome sequencing (WES) was performed on tumor and normal samples from 30 adult AML patients (<65 years) at presentation.
- Bone marrow samples from patients in clinicopathologic remission were analyzed using repeat WES and targeted error-corrected sequencing (MyeloSeq) of 40 recurrently mutated AML genes.
- Analysis focused on detecting patient-specific mutations and assessing variant allele fractions (VAFs) to identify PMD.
Main Results:
- Whole-exome sequencing (WES) detected PMD in 63% of patients (19/30) at a minimum VAF of 2.5%.
- Targeted error-corrected sequencing (MyeloSeq) identified persistent mutations in 77% of patients (23/30) at a VAF >0.1%, showing higher sensitivity.
- MyeloSeq detected additional variants post-chemotherapy in 73% of patients, suggesting new clonal populations, while WES distinguished residual AML from clonal hematopoiesis in some cases.
Conclusions:
- Both PMD and clonal hematopoiesis are prevalent in AML patients achieving first remission.
- Accurate baseline genetic testing is essential for interpreting mutation-based monitoring assays in AML.
- Further clinical trials are needed to correlate complex mutation patterns with clinical outcomes in AML.
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