KIT Asp816Val Mutation Analysis, Blood
Diagnosing systemic mastocytosis
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Systemic mastocytosis is a hematopoietic neoplasm that can be included in the general category of chronic myeloproliferative disorders (CMPDs). These neoplasms are characterized by excessive proliferation of 1 or more myeloid lineages, with cells filling the bone marrow and populating other hematopoietic sites. In systemic mastocytosis, mast cell proliferation is the defining feature, although other myeloid lineages and B cells are frequently part of the neoplastic clone.
Function-altering point mutations in KIT, a gene coding for a membrane receptor tyrosine kinase, have been found in myeloid lineage cells in the majority of systemic mastocytosis cases. The most common KIT mutation is an adenine to thymine base substitution (A->T) at nucleotide position 2468, which results in an aspartic acid to valine change in the protein (Asp816Val). Much less frequently, other mutations at this same location are found and occasional cases with mutations at other locations have also been reported. Mutations at the 816 codon are believed to alter the protein such that it is in a constitutively activated state. The main downstream effect of KIT activation is cell proliferation.
Detection of a mutation at the 816 codon is included as 1 of the minor diagnostic criteria for systemic mastocytosis in the World Health Organization (WHO) classification system for hematopoietic neoplasms and is also of therapeutic relevance, as it confers resistance to imatinib, a drug commonly used to treat CMPDs. It is now clear that individual mast cell neoplasms are variable with respect to the number of cell lineages containing the mutation; some having positivity only in mast cells and others having positivity in additional myeloid and even lymphoid lineages. The mutation has not been reported in normal tissues.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided indicating the mutation status as positive or negative.
The test will be interpreted as positive or negative for KIT Asp816Val.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Some systemic mastocytosis cases may have the mutation only in mast cells. Since these cells rarely circulate in blood and are difficult to obtain in significant numbers from bone marrow aspirate specimens, false-negative results may occur if neoplastic cells are present below the sensitivity of the assay (fewer than 0.01% mutated alleles).
The test is qualitative only. Reliable quantitative results cannot be issued.
The analytic sensitivity of this test is 0.01% and was determined by the dilution of a cell line containing homozygous KIT mutation. This means that 0.01% or greater of the KIT alleles present in the specimen must contain the mutation to be detected by the assay. The analytic specificity was 100% in assay validation.
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Garcia-Montero A, Jara-Acevedo M, Teodosio C, et al: KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood 2006;108:2366-2372
2. Valent P, Akin C, Sperr WR, et al: Diagnosis and treatment of systemic mastocytosis: state of the art. Br J Haematol 2003;122:695-717
3. Jaffe ES, Harris NL, Stein H, et al: World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Haematopoietic and Lymphoid Tissues. 2001, pp 291-302