Error-corrected sequencing strategies enable comprehensive detection of leukemic mutations relevant for diagnosis and minimal residual disease monitoring

BMC Medical Genomics
Erin L CrowgeyTodd E Druley

Abstract

Pediatric leukemias have a diverse genomic landscape associated with complex structural variants, including gene fusions, insertions and deletions, and single nucleotide variants. Routine karyotype and fluorescence in situ hybridization (FISH) techniques lack sensitivity for smaller genomic alternations. Next-generation sequencing (NGS) assays are being increasingly utilized for assessment of these various lesions. However, standard NGS lacks quantitative sensitivity for minimal residual disease (MRD) surveillance due to an inherently high error rate. Primary bone marrow samples from pediatric leukemia (n = 32) and adult leukemia subjects (n = 5), cell line MV4-11, and an umbilical cord sample were utilized for this study. Samples were sequenced using molecular barcoding with targeted DNA and RNA library enrichment techniques based on anchored multiplexed PCR (AMP®) technology, amplicon based error-corrected sequencing (ECS) or a human cancer transcriptome assay. Computational analyses were performed to quantitatively assess limit of detection (LOD) for various DNA and RNA lesions, which could be systematically used for MRD assays. Matched leukemia patient samples were analyzed at three time points; diagnosis, end of induction ...Continue Reading

References

Jun 13, 2015·Haematologica·Jasmijn D E de RooijMaarten Fornerod
Aug 23, 2016·Nature Communications·Andrew L YoungTodd E Druley
Mar 27, 2018·Nature Reviews. Genetics·Jesse J SalkLawrence A Loeb
Mar 31, 2018·The New England Journal of Medicine·Mojca Jongen-LavrencicPeter J M Valk

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Datasets Mentioned

BETA
AB0012

Methods Mentioned

BETA
flow cytometry
PCR

Clinical Trials Mentioned

NCT00372593

Software Mentioned

mummer3
bowtie2
ArcherDx
freeBayes
Fastq
mem
bwa
ExPASy
ArcherDx Analysis platform
Lofreq

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