KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis
Open accessAbstract
Although acquired mutations in KIT are commonly detected in various categories of mastocytosis, the methodologies applied to detect and quantify the mutant type and allele burden in various cells and tissues are poorly defined. We here propose a consensus on methodologies used to detect KIT mutations in patients with mastocytosis at diagnosis and during follow-up with sufficient precision and sensitivity in daily practice. In addition, we provide recommendations for sampling and storage of diagnostic material as well as a robust diagnostic algorithm. Using highly sensitive assays, KIT D816V can be detected in peripheral blood leukocytes from most patients with systemic mastocytosis (SM) that is a major step forward in screening and SM diagnosis. In addition, the KIT D816V allele burden can be followed quantitatively during the natural course or during therapy. Our recommendations should greatly facilitate diagnostic and follow-up investigations in SM in daily practice as well as in clinical trials. In addition, the new tools and algorithms proposed should lead to a more effective screen, early diagnosis of SM and help to avoid unnecessary referrals.
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In some adults and more commonly in children, KIT point mutations other than D816V are found.
“However, in some adults and more commonly in children, other KIT point mutations are found (76,80,81).”
From Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome (2019) · cites this paper as [76]
The Introduction (page unavailable) reports D816V in more than 80% of adult cases but in only one third of affected children, and notes other KIT mutations in both groups. It does not establish that non-D816V *point mutations* are more common in children: the most frequently reported childhood alternative is a deletion. (LLM, conf=0.82)
Experimental — accuracy not yet measuredOver 90% of SM cases harbor the KIT D816V variant, which leads to constitutive activation of receptor tyrosine kinase CD117, responsible for MC survival, proliferation, and differentiation.
“Over 90% of SM cases harbor the KIT D816V variant, that leads to the constitutive activation of the receptor tyrosine kinase CD117, on turn responsible for MC survival, proliferation, and differentiation (37, 38).”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [38]
The Introduction (page unavailable) says KIT D816V occurs in more than 80% of adult cases, with frequency varying by subtype and cell source; it does not support the claim of over 90% of all SM cases. The short overview says D816V keeps the KIT receptor in an active conformation. The Introduction links KIT signaling to mast-cell development, but does not establish the full stated role in survival, proliferation, and differentiation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNGS provides a sensitivity of 1%-5% but remains valuable for detecting rare, non-canonical KIT-activating variants.
“Next-generation sequencing (NGS) provides a sensitivity of 1%–5%; however, it remains valuable for detecting rare, non-canonical KIT-activating variants (38).”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [38]
The Concluding remarks and future perspectives section says NGS may map additional molecular lesions and could complement or replace current KIT mutation analyses. The Introduction also notes rare KIT mutations other than D816V. The paper does not give NGS a 1%–5% sensitivity or specifically establish its value for detecting rare, non-canonical KIT-activating variants; the 0.5%–1% figure in the Standard assays section refers to nested RT-PCR with D-HPLC, not NGS. Page numbers are unavailable in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredIn most adults with systemic mastocytosis, the D816V KIT mutation is detected.
“In most adults with SM, the D816V KIT mutation will be detected.”
From Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome (2019) · cites this paper as [76]
Using highly sensitive allele-specific qPCR, the KIT mutation can be identified in peripheral blood of most patients with systemic mastocytosis.
“Using a highly-sensitive allele-specific qPCR, the mutation can also be identified in the peripheral blood of most patients with SM (73-78).”
From Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome (2019) · cites this paper as [76]
Molecular analysis might yield false-negative results, particularly among patients with a low MC burden or those with KIT mutations other than D816V, in whom a BM biopsy is required to establish the diagnosis.
“Nevertheless, molecular analysis might yield falsenegative results, particularly among patients with a low MC burden or those with KIT mutations other than D816V in whom a BM biopsy is required to establish the diagnosis.21”
From Low Prevalence of Idiopathic Mast Cell Activation Syndrome Among 703 Patients With Suspected Mast Cell Disorders (2024) · cites this paper as [21]
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References 101 · Cited by 290
Research works printed but not linked: 1
- [16]Valent P Horny H-P Li CY Jaffe ES Harris NL Stein H Vardiman JW Mastocytosis World Health Organization (WHO) Classification of Tumours 12001 291 302 IARC Press Lyon, France
- Authors
- Arock, M., Sotlar, K., Akin, C., Broesby-Olsen, S., Hoermann, G., Escribano, L., Kristensen, T. K., Kluin-Nelemans, H. C., Hermine, O., Dubreuil, P., Sperr, W. R., Hartmann, K., Gotlib, J., Cross, N. C. P., Haferlach, T., Garcia-Montero, A., Orfao, A., Schwaab, J., Triggiani, M., Horny, H.-P., Metcalfe, D. D., Reiter, A., & Valent, P.
- Affiliations
- École Normale Supérieure Paris-Saclay (FR)
- Pathologisches Institut (DE)
- Brigham and Women's Hospital (US)
- Medical University of Vienna (AT)
- Universidad de Salamanca (ES)
- Odense University Hospital (DK)
- Hôpital Necker-Enfants Malades (FR)
- Centre National de la Recherche Scientifique (FR)
- University of Cologne (DE)
- Stanford Cancer Institute (US)
- Wessex Regional Genetics Laboratory (GB)
- Munich Leukemia Laboratory (Germany) (DE)
- University Medical Centre Mannheim (DE)
- University of Salerno (IT)
- National Institute of Allergy and Infectious Diseases (US)
- Corresponding author
- Arock, M
- ORCID
- Venue
- Leukemia
- Published
- 2015-02-04
- Volume
- 29
- Issue
- 6
- Pages
- 1223-1232
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- PMC
- PMC4522520
- OpenAlex
- W2097841339
- Cited by
- 290
- References
- 101
- Citations by year
- 2026: 10 · 2025: 25 · 2024: 20 · 2023: 29 · 2022: 31 · 2021: 32 · 2020: 25 · 2019: 31 · 2018: 32 · 2017: 25 · 2016: 20 · 2015: 9
- FWCI
- 2.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Leukemia (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- PubMed Central (acceptedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- edoc (University of Basel) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal Tumor Research and Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Veterinary Oncology Research
- Keywords
- KIT mutations, mastocytosis, systemic mastocytosis, KIT D816V, allele burden, mutation detection, diagnostic algorithm, peripheral blood leukocytes, mast cell neoplasms
- MeSH terms
- Animals, DNA Mutational Analysis, Europe, Humans, Mast Cells, Mastocytosis, Mutation, Neoplasms, Proto-Oncogene Proteins c-kit
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