Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.
Mastocytosis comprises a group of diseases in which excessive amounts of pathologic mast cells proliferate and accumulate in the tissues.1 In individuals with systemic mastocytosis (SM), focal and/or diffuse infiltrates of neoplastic mast cells are seen in the bone marrow, liver, spleen, and gastrointestinal tract.2
Mastocytosis is linked to somatic gain-of-function point mutations in KIT in about 90% of cases. However, somatic mutations in other genes, such as SRSF2, ASXL1, RUNX1, and EZH2, and loss of function of SETD2 may influence the disease course, particularly in aggressive types of SM. Thus, a tailored approach to therapy is warranted.3
Most cases of SM are sporadic (not inherited), occurring in people with no family history of the condition. Because the genetic mutations are not present in germ cells, they are not passed on to the next generation. A few studies have documented SM in more than one family member. In such cases, the disease is inherited in an autosomal-dominant pattern. A person with this type of SM has a 50% chance of passing the mutation on to each child.4
Mutation of c-kit at Codon 816
Mast cells, hematopoietic stem cells, melanocytes, germ cells, and gastrointestinal stromal cells all express KIT, which belongs to the receptor tyrosine kinase family. The intensity of KIT expression on mast cell membranes is substantially higher than that on other cells. The c-kit proto-oncogene encodes KIT.5 The proto-oncogene has 21 exons and is found on the long arm of chromosome 4 (4q11-4q13). KIT encodes a type III tyrosine kinase receptor. More than 90% of the KIT gene mutations responsible for SM arise in exon 17, although some mutations may occur in exons 8, 9, 10, and 11. In SM, constitutive receptor activation due to KIT mutations causes mast cells to proliferate, differentiate, survive, migrate, and produce cytokines. The most common activating loop mutation in KIT is p.D816V. As a result of this mutation, aspartic acid is replaced by valine at codon 816 in the kinase activation loop domain of the protein, causing its constitutive activation. The p.D816V mutation is seen in more than 80% of adults with SM and in more than 90% of patients with indolent SM. Other KIT mutations affecting the same codon, such as D816Y, D816F, D816H, and D816I, have been found less frequently in patients with SM.3,6,7
Alternative KIT mutations are commonly seen in patients with advanced SM, mast cell leukemia, or mast cell sarcoma. These variants are generally found in the juxtamembrane domain, such as KIT p.V560G, or the extracellular domain, such as KIT p.Del419. In addition, some patients with SM have no identifiable KIT variants (KIT wild type); this is especially true in nearly 70% of cases of well-differentiated SM, a subset of indolent SM defined by the presence of compact, multifocal infiltrates of round, mature, CD2- and CD25-negative mast cells in the bone marrow.6
Other Genetic Abnormalities
The introduction of next-generation sequencing has allowed a broader molecular characterization of SM beyond the role of KIT mutation. Additional somatic mutations (eg,TET2, SRSF2, ASXL1, EZH2, CBL, RUNX1, and RAS) have been noted in 90% of cases of advanced SM, particularly SM associated with a hematologic neoplasm (SM-AHN). In a series of 70 cases of ASM, the most common mutated genes demonstrated by next-generation sequencing were TET2 (47%), SRSF2 (43%), ASXL1 (29%), RUNX1 (23%), JAK2 V617F (16%), NRAS/KRAS (14%), CBL (13%), and EZH2 (10%). Other, less commonly found mutated genes were IDH2, ETV6, U2AF1, SF3B1, MLL, NPM1, DNMT3A, and TP53. SRSF2 and ASXL1 mutations are independent negative predictors of overall survival.3
The human SETD2 gene is found on cytogenetic band p21.31 of chromosome 3, which is commonly affected by copy number loss in malignancies. A study of 53 patients with SM detected loss-of-function mutations of SETD2.8
Many of the additional chromosomal defects have been identified in patients with myeloid neoplasm in addition to SM. Hypereosinophilic syndrome and chronic eosinophilic leukemia are usually linked to mutations in the platelet-derived growth factor receptor A (PDGFRA) and PDGFRB genes that result in formation of the Fip1-like-1 (FIP1L1)-PDGFRA fusion gene. The FIP1L1-PDGFRA fusion gene was found in half of patients with SM and significant eosinophilia.5
- Gangireddy M, Ciofoaia GA. Systemic mastocytosis. StatPearls [Internet]. Published July 21, 2021. Accessed April 13, 2022.
- Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 2017;129(11):1420-1427. doi:10.1182/blood-2016-09-731893
- Nicolosi M, Patriarca A, Andorno A, et al. Precision medicine in systemic mastocytosis. Medicina (Kaunas). 2021;57(11):1135. doi:10.3390/medicina57111135
- Systemic mastocytosis. Genetic and Rare Diseases Information Center (GARD). Updated June 9, 2016. Accessed April 13, 2022.
- Ozdemir D, Dagdelen S, Erbas T. Systemic mastocytosis. Am J Med Sci. 2011;342(5):409-415. doi:10.1097/MAJ.0b013e3182121131
- Nedoszytko B, Arock M, Lyons JJ, et al. Clinical impact of inherited and acquired genetic variants in mastocytosis. Int J Mol Sci. 2021;22(1):411. doi:10.3390/ijms22010411
- Genetic testing – mastocytosis skin; urticaria pigmentosa (cutaneous mastocytosis). Gen KIT. IVAMI (Instituto Valenciano de Microbiologia). Accessed April 13, 2022.
- Martinelli G, Mancini M, De Benedittis C, et al. SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis. Leukemia. 2018;32(1):139-148. doi:10.1038/leu.2017.183
Reviewed by Hasan Avcu, MD, on 4/29/2022.