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Mol Diagn Ther. 2019 Dec;23(6):791-802. doi: 10.1007/s40291-019-00436-8.

Clinical Validation and Implementation of a Measurable Residual Disease Assay for NPM1 in Acute Myeloid Leukemia by Error-Corrected Next-Generation Sequencing.

Author information

1
Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago Medicine, Chicago, IL, USA. lritterhouse@partners.org.
2
Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. lritterhouse@partners.org.
3
Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago Medicine, Chicago, IL, USA.

Abstract

BACKGROUND:

Nucleophosmin 1 (NPM1) is one of the most commonly mutated genes in acute myeloid leukemia, with mutations observed in approximately 30% of all adult cases. The persistence of NPM1 mutations following chemotherapy is associated with a greater risk of relapse as well as a lower rate of survival, making NPM1 measurable residual disease (MRD) an informative clinical target.

METHODS:

Herein, we have developed a straightforward unique molecular identifier (UMI)-based amplicon next-generation sequencing method for the detection of NPM1-mutated MRD that addresses some of the limitations present in other assays.

RESULTS:

The NPM1 assay allowed for accurate counting of individual mutant and wild-type molecules down to 0.01% variant allelic frequency. In silico contamination experiments highlighted the ability of this UMI methodology to maximize specificity through dramatic reductions in sequencing/demultiplexing bleed-through error.

CONCLUSION:

Performance and clinical utility of the NPM1 MRD assay are established via both validation experiments and analyses of live performance over 1.5 years of routine clinical service.

PMID:
31673932
DOI:
10.1007/s40291-019-00436-8

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