Digital PCR: A Sensitive and Precise Method for KIT D816V Quantification in Mastocytosis
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Abstract BACKGROUND The analytically sensitive detection of KIT D816V in blood and bone marrow is important for diagnosing systemic mastocytosis (SM). Additionally, precise quantification of the KIT D816V variant allele fraction (VAF) is relevant clinically because it helps to predict multilineage involvement and prognosis in cases of advanced SM. Digital PCR (dPCR) is a promising new method for sensitive detection and accurate quantification of somatic mutations. METHODS We performed a validation study of dPCR for KIT D816V on 302 peripheral blood and bone marrow samples from 156 patients with mastocytosis for comparison with melting curve analysis after peptide nucleic acid-mediated PCR clamping (clamp-PCR) and allele-specific quantitative real-time PCR (qPCR). RESULTS dPCR showed a limit of detection of 0.01% VAF with a mean CV of 8.5% and identified the mutation in 90% of patients compared with 70% for clamp-PCR (P < 0.001). Moreover, dPCR for KIT D816V was highly concordant with qPCR without systematic deviation of results, and confirmed the clinical value of KIT D816V VAF measurements. Thus, patients with advanced SM showed a significantly higher KIT D816V VAF (median, 2.43%) compared with patients with indolent SM (median, 0.14%; P < 0.001). Moreover, dPCR confirmed the prognostic significance of a high KIT D816V VAF regarding survival (P < 0.001). CONCLUSIONS dPCR for KIT D816V provides a high degree of precision and sensitivity combined with the potential for interlaboratory standardization, which is crucial for the implementation of KIT D816V allele burden measurement. Thus, dPCR is suitable as a new method for KIT D816V testing in patients with mastocytosis.
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Increased sensitivity of methodology has shown comparable results for mutational testing on BM and PB, with a discordance rate ranging from 5% to 10%.
“the increased sensitivity of the methodology has shown comparable results for mutational testing on BM and PB, with a discordance rate ranging from 5% to 10% (40, 42, 45, 46).”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [42]
The Results report a strong correlation (r = 0.978) between KIT D816V measurements in simultaneously obtained bone marrow and peripheral blood samples, and the Discussion says their detection-rate differences were not significant. The paper does not report a 5%–10% discordance rate between those specimens; its 96% concordance figure compares ddPCR with qPCR, not bone marrow with peripheral blood. (LLM, conf=0.89)
Experimental — accuracy not yet measuredCurrently, the gold standard techniques are ASO-qPCR or, preferably, ddPCR, both achieving a sensitivity of 0.001%.
“Currently, the gold standard techniques are ASO-qPCR or, preferably, droplet digital PCR (ddPCR), both of which achieve a sensitivity of 0.001% (42).”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [42]
The Discussion (page not provided) calls highly sensitive PCR-based testing the gold standard for KIT D816V, but describes ddPCR as a promising method that might become a new standard, not an established preferred one. It reports a ddPCR LOD95 of 0.01% VAF, not 0.001%; the earlier allele-specific qPCR assay's reported limit corresponds to approximately 0.0015% VAF. The Results (page not provided) say combining 10 ddPCR wells improved sensitivity, without establishing a 0.001% LOD95. (LLM, conf=0.90)
Experimental — accuracy not yet measured
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- Authors
- Greiner, G., Gurbisz, M., Ratzinger, F., Witzeneder, N., Simonitsch-Klupp, I., Mitterbauer-Hohendanner, G., Mayerhofer, M., Müllauer, L., Sperr, W. R., Valent, P., & Hoermann, G.
- Affiliations
- Medical University of Vienna (AT)
- Department of Pathology, Medical University of Vienna, Vienna, Austria
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
- Hanusch Hospital (AT)
- Ludwig Boltzmann Institute for Hematology and Oncology (AT)
- Corresponding author
- Hoermann, Gregor
- ORCID
- Venue
- Clinical Chemistry
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-03-01
- Volume
- 64
- Issue
- 3
- Pages
- 547-555
- ISSN
- 0009-9147 (ISSN-L)
- 1530-8561
- PMC
- PMC7115889
- OpenAlex
- W2772880658
- Cited by
- 83
- References
- 42
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 8 · 2023: 13 · 2022: 10 · 2021: 11 · 2020: 8 · 2019: 3 · 2018: 2
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Clinical Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal Tumor Research and Treatment
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Keywords
- digital PCR, KIT D816V mutation, systemic mastocytosis, variant allele frequency, bone marrow, peripheral blood, prognostic factors, survival, assay validation
- MeSH terms
- Adult, Aged, Aged, 80 and over, Bone Marrow, DNA Mutational Analysis, Female, Humans, Male, Mastocytosis, Middle Aged, Mutation, Sensitivity and Specificity, Reproducibility of Results, Polymerase Chain Reaction, Proto-Oncogene Proteins c-kit, Limit of Detection, Real-Time Polymerase Chain Reaction
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