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Patient-Specific Assays Based on Whole-Genome Sequencing Data to Measure Residual Disease in Children With Acute Lymphoblastic Leukemia : A Proof of Concept Study

Arthur, Cecilia (author)
Karolinska Institutet
Rezayee, Fatemah (author)
Karolinska Institutet
Mogensen, Nina (author)
Karolinska Institutet
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Saft, Leonie (author)
Karolinska Institutet
Rosenquist, Richard (author)
Karolinska Institutet
Nordenskjoeld, Magnus (author)
Karolinska Institutet
Harila-Saari, Arja H. (author)
Uppsala universitet,Barnonkologisk och neurologisk forskning
Tham, Emma (author)
Karolinska Institutet
Barbany, Gisela (author)
Karolinska Institutet
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 (creator_code:org_t)
2022-07-05
2022
English.
In: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 12
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Risk-adapted treatment in acute lymphoblastic leukemia (ALL) relies on genetic information and measurable residual disease (MRD) monitoring. In this proof of concept study, DNA from diagnostic bone marrow (BM) of six children with ALL, without stratifying genetics or central nervous system (CNS) involvement, underwent whole-genome sequencing (WGS) to identify structural variants (SVs) in the leukemic blasts. Unique sequences generated by SVs were targeted with patient-specific droplet digital PCR (ddPCR) assays. Genomic DNA (gDNA) from BM and cell-free DNA (cfDNA) from plasma and cerebrospinal fluid (CSF) were analyzed longitudinally. WGS with 30x coverage enabled target identification in all cases. Limit of quantifiability (LoQ) and limit of detection (LoD) for the ddPCR assays (n = 15) were up to 10(-5) and 10(-6), respectively. All targets were readily detectable in a multiplexed ddPCR with minimal DNA input (1 ng of gDNA) at a 10(-1) dilution, and targets for half of the patients were also detectable at a 10(-2) dilution. The level of MRD in BM at end of induction and end of consolidation block 1 was in a comparable range between ddPCR and clinical routine methods for samples with detectable residual disease, although our approach consistently detected higher MRD values for patients with B-cell precursor ALL. Additionally, several samples with undetectable MRD by flow cytometry were MRD-positive by ddPCR. In plasma, the level of leukemic targets decreased in cfDNA over time following the MRD level detected in BM. cfDNA was successfully extracted from all diagnostic CSF samples (n = 6), and leukemic targets were detected in half of these. The results suggest that our approach to design molecular assays, together with ddPCR quantification, is a technically feasible option for accurate MRD quantification and that cfDNA may contribute valuable information regarding MRD and low-grade CNS involvement.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Klinisk laboratoriemedicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Clinical Laboratory Medicine (hsv//eng)

Keyword

acute lymphoblastic leukemia
liquid biopsy
disease monitoring
precision medicine
whole-genome sequencing
structural variation
technical feasibility
diagnostic performance

Publication and Content Type

ref (subject category)
art (subject category)

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