Mastocytosis
Mastocytosis is a rare and complex hematologic disorder characterized by the abnormal accumulation of mast cells in various tissues, leading to a broad spectrum of clinical manifestations and outcomes . [1], [2] While often driven by a common somatic oncogenic mutation, particularly in the KIT gene, its genetic predisposition is not fully understood . [1], [2]
Biological Basis
The primary biological basis of mastocytosis involves an activating somatic mutation, most frequently KIT D816V, which leads to uncontrolled mast cell proliferation and survival. [1] However, constitutional genetic variation, referring to inherited genetic differences, also plays a significant role in the disease's heterogeneity and susceptibility. [1] In advanced forms of systemic mastocytosis (SM), additional recurrent somatic mutations in genes like TET-2, DNMT3A, and ASXL1 are frequently observed, affecting processes such as splicing, signaling, and epigenetics. [2] Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with mastocytosis, including intergenic SNPs like rs4616402, rs4662380, and rs13077541. [1] Other associated SNPs have been found in genes such as ABCA2 (rs80138802), OTX2-AS1 (rs11845537), HLA-V (rs1611207), PDE4DIP (rs1778155), FTCD (rs61735841), OR51Q1 (rs10838094), CYP2B6 (rs2279343), and RPTN (rs76015112), as well as near the RP11 gene (rs9828758). [2] These genetic variations may influence mastocytosis by promoting the outgrowth of KIT D816V positive clones, increasing the likelihood of a KIT D816V mutation arising, or affecting the development of clinical signs and symptoms. [1]
Clinical Relevance
Mastocytosis presents with a wide array of clinical phenotypes, ranging from cutaneous mastocytosis (CM) primarily affecting the skin, to various forms of systemic mastocytosis (SM) that can involve internal organs . [1], [2] The identification of specific SNPs associated with mastocytosis and its subgroups holds significant clinical relevance, potentially offering insights into disease pathogenesis, prognosis, and therapeutic stratification. [2] For instance, rs4616402 has been associated with age at presentation in individuals with non-advanced disease, where each risk allele may increase the age of onset by approximately 4.41 years. [1] Understanding these genetic associations can help explain the observed heterogeneity in patient outcomes and guide more personalized treatment approaches.
Social Importance
As a rare disease, mastocytosis poses unique challenges for affected individuals and healthcare systems. The complex nature of the disorder and its varied clinical presentations often lead to diagnostic delays and difficulties in management. Research into the genetic underpinnings of mastocytosis, particularly through GWAS, is crucial for advancing our understanding of its etiology and progression. [1] Identifying validated genetic markers can provide new avenues for investigation, potentially leading to improved diagnostic tools, risk stratification, and the development of targeted therapies . [1], [2] This genetic research is vital for enhancing patient care and improving the quality of life for those living with mastocytosis.
Methodological and Statistical Considerations
The relatively modest cohort sizes employed in some genome-wide association studies (GWAS) for mastocytosis, particularly when analyzing patient subgroups, inherently limit the statistical power to detect all relevant genetic associations and can lead to inflated effect sizes. This constraint makes it challenging to draw definitive conclusions regarding the pathogenic impact of identified single nucleotide polymorphisms (SNPs) without further validation. [2] The observed replication gaps, where some previously reported associations were not confirmed, underscore the need for larger, independent prospective studies to verify current findings and enhance confidence in their generalizability. [1] Furthermore, the absence of preclinical models exploring the functional roles of many newly identified SNPs represents a significant knowledge gap, impeding a comprehensive understanding of their biological mechanisms.
Phenotypic Specificity and Population Generalizability
While studies deliberately focused on specific mastocytosis subtypes, such as KIT D816V positive cases, to achieve genetic homogeneity, this approach inherently restricts the generalizability of findings to the broader spectrum of mastocytosis, including KIT D816V negative forms. [1] Mastocytosis itself is a complex disorder characterized by a wide range of clinical phenotypes and outcomes, meaning genetic associations identified within a narrow definition may not fully explain the disease's overall heterogeneity. [1] The predominant recruitment of participants from European populations in these studies also limits the direct applicability of findings to individuals of other ancestries, potentially overlooking population-specific genetic risk factors or leading to biased risk estimates in diverse groups. [1] Additionally, the broad range of clinical phenotypes, such as cutaneous versus systemic mastocytosis, or indolent versus advanced forms, adds complexity, and associations with specific clinical characteristics are not always robust across cohorts.
Unexplored Biological Mechanisms and Gene-Environment Interactions
Many of the identified susceptibility loci for mastocytosis are located in intergenic regions or exhibit only weak evidence for direct functional consequences, highlighting a critical need for in-depth functional annotation and mechanistic studies. [1] The current understanding of how these constitutional genetic variations interact with known somatic mutations, such as KIT D816V, or with potential environmental factors, remains incomplete. [1] While hypotheses exist regarding how genetic variation might influence mastocytosis—for instance, by promoting clonal outgrowth or increasing mutation probability—these mechanisms require extensive empirical investigation to elucidate the full biological pathways leading to disease development and progression. [1] The lack of association between genetic variation at KIT and the acquisition of KIT D816V, unlike observations in other myeloproliferative neoplasms, indicates a specific knowledge gap regarding the initial mutational events in mastocytosis.
Variants
Genetic variations play a crucial role in modulating an individual's susceptibility to mastocytosis, a complex disorder characterized by the abnormal proliferation of mast cells. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with varying frequencies in mastocytosis patients compared to controls, suggesting their involvement in the disease's pathogenesis. [2] These variants can influence gene activity, protein function, or regulatory pathways, contributing to the diverse clinical presentations of mastocytosis.
Several variants have been found to be more prevalent in mastocytosis patients. The rs80138802 polymorphism is located within the ABCA2 gene, which encodes an ATP-binding cassette transporter involved in lipid and cholesterol transport. [2] This variant shows a significantly higher frequency in mastocytosis, particularly in cutaneous mastocytosis (CM) in both adults and children, exhibiting a recessive mode of inheritance. [2] Similarly, rs11845537 is found within the OTX2-AS1 gene, a long non-coding RNA known to regulate gene expression, and is also more frequently detected in CM patients. [2] Another associated variant, rs1611207 in the HLA-V gene, part of the major histocompatibility complex (MHC), suggests an immune system involvement as MHC proteins are critical for presenting antigens and orchestrating immune responses. [2] The rs1778155 variant in PDE4DIP, which helps localize phosphodiesterases and regulate cellular signaling, is also more prevalent, indicating potential alterations in mast cell activation and proliferation pathways. [2] These findings highlight diverse genetic contributions to mast cell dysregulation and disease development.
Conversely, some genetic variants appear less frequently in individuals with mastocytosis, potentially offering a protective effect or indicating a different disease mechanism. The rs10838094 polymorphism in OR51Q1, an olfactory receptor gene expressed in various non-olfactory tissues, is significantly less common in mastocytosis patients, including children with CM. [2] This suggests its normal function might inhibit mast cell expansion or activity. Likewise, rs2279343 in CYP2B6, a cytochrome P450 enzyme primarily involved in metabolizing drugs and endogenous compounds, is less frequently observed in mastocytosis, especially in CM patients. [2] This variant's reduced frequency could imply that its presence or normal metabolic function influences pathways that are protective against mastocytosis development. The rs9828758 polymorphism, found near the RP11 gene, is also less frequent in mastocytosis patients, particularly in children with CM, suggesting a potential role in modulating disease risk. [2]
Further studies have identified specific intergenic SNPs associated with KIT D816V positive mastocytosis, a common oncogenic driver mutation in the disease. The rs4616402 variant, located in an intergenic region, is strongly associated with the expression of CEBPA, a crucial transcription factor for myeloid differentiation and granulopoiesis. [1] This variant increases the risk of developing mastocytosis and is predicted to alter transcription factor binding motifs, influencing the expression of CEBPA, which is vital for normal blood cell development and could impact aberrant mast cell differentiation. [1] Another significant intergenic variant, rs4662380, increases the risk of mastocytosis and is located within the first intron of LINC01412, a long non-coding RNA. [1] These findings underscore the complex genetic landscape of mastocytosis, where both coding and non-coding variants contribute to disease susceptibility and phenotype.
There is no information about the management, treatment, or prevention of mastocytosis in the provided research.
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs80138802 | ABCA2 | mastocytosis |
| rs10838094 | HBE1, OR51B5, HBG2, OR51Q1 | mastocytosis |
| rs11845537 | OTX2-AS1, RPL3P3, LINC03059 | mastocytosis |
| rs9828758 | PRDX5P1 - LINC02005 | mastocytosis |
| rs4616402 | SLC7A10 - CEBPA | mastocytosis hematological measurement |
| rs1611207 | HLA-F-AS1, HCG4, HLA-V, HLA-V | mastocytosis rheumatoid arthritis, hypothyroidism |
| rs4662380 | LINC01412 | mastocytosis |
| rs1778155 | PDE4DIP | mastocytosis |
| rs2279343 | CYP2B6 | mastocytosis |
| rs45487695 | MOCS1 | mastocytosis |
Biological Background of Mastocytosis
Mastocytosis is a rare and complex myeloid neoplasm characterized by the abnormal expansion and accumulation of mast cells within various tissues and organs. [1] This uncontrolled proliferation of mast cells can affect multiple systems, including the skin, bone marrow, liver, spleen, and gastrointestinal tract, leading to a wide range of clinical presentations and disease outcomes. [1] The severity and location of mast cell infiltration form the basis for classifying mastocytosis into different subtypes, such as cutaneous mastocytosis (CM), primarily affecting children, and systemic mastocytosis (SM), commonly seen in adults with bone marrow involvement. [1]
Mast Cell Biology and Pathophysiology
Mast cells are critical components of the immune system, known for their role in allergic reactions and host defense, primarily through the release of various mediators upon activation. [3] In mastocytosis, a fundamental pathophysiological event is the clonal expansion of these mast cells, driven predominantly by a somatic gain-of-function mutation in the KIT gene, specifically D816V. [1] This KIT D816V mutation results in a constitutively active KIT receptor, a transmembrane tyrosine kinase that plays a vital role in mast cell development, survival, and function, thereby leading to uncontrolled mast cell growth and accumulation. [4] The excessive number of mast cells and their aberrant activation contribute to the diverse clinical manifestations, including skin lesions, gastrointestinal symptoms, and systemic reactions, which can range from relatively benign forms like indolent systemic mastocytosis (ISM) to more aggressive variants such as aggressive systemic mastocytosis (ASM) and mast cell leukemia. [5]
Genetic Predisposition and Driver Mutations
While the somatic KIT D816V mutation is a primary oncogenic driver in over 80% of mastocytosis cases, constitutional genetic variations also play a significant role in disease predisposition and phenotypic heterogeneity. [1] Unlike the somatic KIT D816V mutation, which is generally not germline transmissible, inherited genetic factors can influence an individual's susceptibility to developing mastocytosis or modulate its clinical course. [1] These germline variants may contribute to disease development through several mechanisms: by promoting the outgrowth of KIT D816V-positive mast cell clones, by increasing the likelihood of a KIT D816V mutation arising in a stem cell, or by influencing the severity and presentation of symptoms in individuals with existing KIT D816V-positive clones. [1] Furthermore, in advanced systemic mastocytosis, additional recurrent somatic mutations in genes like TET2, DNMT3A, and ASXL1, which regulate epigenetic processes, splicing, and signaling, have been identified, highlighting the complex genetic landscape of the disorder. [2]
Molecular Pathways and Regulatory Networks
Beyond the central role of the KIT receptor, various molecular pathways and regulatory networks are implicated in the pathogenesis of mastocytosis. Cytokines and their receptors are crucial mediators of mast cell function and are often found to have altered expression or genetic polymorphisms in affected individuals. [2] For instance, single nucleotide polymorphisms (SNPs) in genes encoding interleukin-6 (IL6) and its receptor (IL6R), interleukin-13 (IL13), and interleukin-31 (IL31) have been associated with different forms or clinical features of mastocytosis. [6] Additionally, components of the innate immune system, such as Toll-like receptors, including a nonfunctional variant of Toll-Like Receptor 2 (TLR2), have been investigated for their potential involvement in disease pathogenesis, suggesting a broader dysregulation of immune signaling. [2] These molecular abnormalities contribute to the aberrant proliferation and activation of mast cells, driving the diverse pathophysiological processes observed in mastocytosis.
Genetic Polymorphisms and Disease Heterogeneity
Recent genome-wide association studies (GWAS) have unveiled novel genetic polymorphisms that contribute to the heterogeneity of mastocytosis, further elucidating the complex interplay between inherited and acquired factors. [1] For example, specific SNPs like rs4616402, rs4662380, and rs13077541 have been identified as susceptibility loci, with some variants showing associations with clinical features such as age at presentation. [1] These SNPs are located near genes like EXOC2, ASXL2, TEX41, and TBL1XR1, which are involved in diverse cellular functions, including gene expression regulation and immune cell activity. [1] Other genes, such as ABCA2, OTX2-AS1, HLA-V, and PDE4DIP, have also been found to harbor polymorphisms that are more frequently present in mastocytosis patients, while variants in FTCD, OR51Q1, CYP2B6, RPTN, and near RP11 are less common. [2] These findings underscore that while a predominant somatic mutation drives the disease, germline genetic variations modify disease risk, influence its phenotypic expression, and contribute to the wide spectrum of clinical outcomes observed in mastocytosis. [1]
Oncogenic KIT Signaling and Mast Cell Proliferation
Mastocytosis is primarily driven by dysregulation of the KIT receptor tyrosine kinase signaling pathway, most notably through the somatic KIT D816V mutation found in over 80% of affected individuals. [1] This specific mutation leads to constitutive, ligand-independent activation of the KIT receptor, bypassing normal regulatory feedback loops and initiating persistent intracellular signaling cascades. The uncontrolled activation of downstream pathways promotes sustained mast cell proliferation, survival, and accumulation in various tissues, forming the hallmark of the disease. [4] The central role of aberrant KIT signaling also positions it as a critical therapeutic target, with tyrosine kinase inhibitors designed to block this hyperactive pathway, though the D816V mutation confers resistance to some inhibitors like imatinib. [7]
Immune and Inflammatory Cytokine Networks
Beyond KIT, a network of immune and inflammatory signaling pathways contributes to the complex pathogenesis of mastocytosis. Polymorphisms in cytokine genes and their receptors, such as IL6 and its receptor, have been identified as potentially influencing disease susceptibility. [6] Similarly, variants in the IL4 receptor alpha chain (e.g., Q576R) are associated with indolent cutaneous forms of mastocytosis, while IL13 promoter gene polymorphisms (e.g., -1112C/T and rs1800925) are linked to systemic mastocytosis and altered interleukin-13 levels. [8] Furthermore, IL31 polymorphisms and serum IL31 levels correlate with clinical manifestations and pruritus, indicating the role of diverse cytokine-mediated signaling in modulating disease presentation and severity. [9] Additionally, a gene variant coding for a nonfunctional Toll-like receptor 2 (TLR2) may contribute to the pathogenic mechanisms, suggesting altered innate immune responses in mastocytosis. [10]
Genetic Predisposition and Gene Regulatory Mechanisms
Germline genetic variations play a significant role in predisposing individuals to mastocytosis, particularly the KIT D816V positive subtype, by influencing gene regulation and expression. A genome-wide association study identified several intergenic single nucleotide polymorphisms (SNPs) associated with mastocytosis risk, including rs4616402, rs4662380, and rs13077541. [1] Specifically, rs4616402 is linked to the expression of CEBPA, a transcription factor crucial for myelopoiesis, suggesting that altered CEBPA levels could affect mast cell development and expansion. [1] Other SNPs, such as rs4662380, are associated with the expression of the long non-coding RNA gene TEX41, and rs13077541 with TBL1XR1 (transducin (b)-like 1 X-linked receptor 1), indicating complex regulatory effects on gene networks. [1] Suggestive associations were also found with genetic variation at TERT (telomerase reverse transcriptase), TPSAB1/TPSB2 (encoding tryptases), and IL13, further highlighting how inherited genetic factors can modulate gene regulation and contribute to the heterogeneity of mastocytosis phenotypes. [1]
Epigenetic Dysregulation and Cellular Transport Pathways
Epigenetic modifications represent another layer of regulatory mechanisms implicated in mastocytosis, influencing gene expression without altering the underlying DNA sequence. Several genes involved in epigenetic processes, such as TET2, DNMT3A, ASXL1, and CBL, have been found to harbor mutations in systemic mastocytosis. [2] These genes are critical regulators of DNA methylation and chromatin remodeling, suggesting that their dysregulation can lead to aberrant gene expression patterns that promote mast cell clonality and expansion. [11] In addition to these intrinsic regulatory pathways, cellular transport mechanisms also play a role, with ABCA2 (ATP-binding Cassette transporter-2) identified as a potential therapeutic target. [12] While the specific contribution of ABCA2 to mastocytosis pathogenesis is not fully detailed, its function as a transporter suggests potential involvement in metabolic flux control, drug resistance, or the movement of molecules essential for mast cell survival and function, offering an avenue for targeted intervention.
Genetic Predisposition and Diagnostic Utility
Genome-wide association studies (GWAS) have identified novel germline single nucleotide polymorphisms (SNPs) that predispose individuals to KIT D816V positive mastocytosis, shedding light on the genetic underpinnings of this complex disorder. [1] Three intergenic SNPs, rs4616402, rs4662380, and rs13077541, reached genome-wide significance, with rs4616402 notably associated with the expression of CEBPA, a key transcription factor in myelopoiesis. [1] These findings highlight constitutional genotype as an additional factor contributing to mastocytosis heterogeneity and offer potential for enhanced diagnostic utility by identifying individuals with a genetic predisposition, even in the presence of the common KIT D816V somatic mutation. [1] Additionally, other identified SNPs, such as rs10838094 in OR51Q1 and rs80138802 in ABCA2, demonstrate varying prevalence in mastocytosis patients compared to controls, suggesting their role as potential markers for disease presence across different mastocytosis variants. [2]
Risk Stratification and Prognostic Implications
The identification of specific germline variants offers valuable insights for risk stratification and predicting disease course in mastocytosis. For instance, the SNP rs4616402 has been significantly associated with an increased age at presentation in individuals with non-advanced mastocytosis, with each risk allele correlating with an average increase of 4.41 years in age of onset. [1] While this association was not observed in the smaller cohort of advanced disease patients, suggesting potential confounding by additional somatic mutations, it underscores the role of germline genetics in influencing early disease phenotype. [1] Furthermore, suggestive associations at loci like TERT, including rs2853677 and the established cancer risk SNP rs7726159, imply a genetic predisposition that could inform the long-term monitoring and personalized management strategies for individuals with mastocytosis, particularly in assessing the potential for disease progression. [1] These genetic markers may contribute to a more nuanced prediction of outcomes, complementing the established WHO classification criteria that differentiate between indolent forms and those with a higher risk of aggression. [2]
Disease Heterogeneity and Associated Conditions
Mastocytosis is characterized by a broad spectrum of clinical phenotypes and outcomes, despite frequently sharing a common KIT D816V somatic mutation, and constitutional genetic variations contribute significantly to this heterogeneity. [1] GWAS have identified specific SNPs that are differentially prevalent across various WHO subgroups, including cutaneous and systemic mastocytosis, suggesting distinct genetic influences on disease presentation and progression. [2] Beyond mastocytosis itself, certain identified genetic loci have implications for related conditions; for example, rs7726159 at the TERT locus is an established risk SNP for multiple cancer types, while rs1800925 in IL13 has been linked to inflammatory disorders such as chronic obstructive pulmonary disease, as well as adult systemic mastocytosis and serum interleukin-13 levels. [1] These associations underscore the complex interplay between germline genetics and the diverse clinical manifestations and comorbidities observed in the mastocytosis patient population, providing avenues for understanding overlapping phenotypes and potential complications. [1]
Frequently Asked Questions About Mastocytosis
These questions address the most important and specific aspects of mastocytosis based on current genetic research.
1. If I have mastocytosis, will my kids get it too?
It's complex, but some inherited genetic differences do play a role in mastocytosis susceptibility. While a common activating mutation like KIT D816V usually arises spontaneously, constitutional genetic variations passed down from parents can increase the likelihood of developing the disease or influence its characteristics. Research is ongoing to fully understand these inherited factors.
2. Why does my mastocytosis seem so different from someone else's?
Mastocytosis has a wide range of clinical presentations, from skin-only issues to more severe forms affecting internal organs. This difference, called heterogeneity, is partly due to various genetic factors. For instance, specific inherited genetic variations (SNPs) can influence how the disease develops and even affect the clinical signs and symptoms you experience.
3. Why did I get mastocytosis later in life than some others?
Your age at presentation can be influenced by specific genetic variations. For example, a particular genetic marker, rs4616402, has been associated with the age of onset in non-advanced disease. Each "risk allele" you carry for this marker could potentially increase your age of onset by approximately 4.41 years.
4. Could a DNA test help my doctor treat my mastocytosis?
Yes, identifying specific genetic variations, like certain SNPs (e.g., rs4662380 or rs13077541), is becoming increasingly relevant. These insights can help your doctor understand the disease's development, predict its course, and guide more personalized treatment choices for you. This genetic information can help stratify patients for different therapies.
5. Does my ancestry change my mastocytosis risk?
It's possible. Most genetic studies on mastocytosis have predominantly recruited participants from European populations. This means that specific genetic risk factors unique to other ancestries might be overlooked, or current risk estimates might not apply directly to individuals from different backgrounds. More research across diverse populations is needed to fully understand this.
6. Is mastocytosis something I inherited or did I just get it?
Mastocytosis primarily involves an activating somatic mutation, most commonly KIT D816V, which means it usually arises spontaneously in your body's cells and isn't inherited. However, inherited genetic differences, called constitutional genetic variations, can significantly influence your susceptibility to developing the disease or how it progresses.
7. Why do some people's mastocytosis get worse than others?
The progression and severity of mastocytosis can vary greatly. In advanced forms, additional somatic mutations in genes like TET-2, DNMT3A, and ASXL1 are often observed, which can contribute to the disease worsening. Furthermore, specific inherited genetic variations can also influence patient outcomes and the overall heterogeneity of the disease.
8. Why is mastocytosis so hard for doctors to diagnose?
Mastocytosis is a rare disease with a broad and complex range of symptoms that can affect different parts of the body. This varied presentation often leads to diagnostic delays and difficulties in management. Understanding the underlying genetic factors is crucial for developing better diagnostic tools, but its complex nature makes diagnosis challenging.
9. Are new treatments for mastocytosis coming out soon?
Research into the genetic causes of mastocytosis, especially through genome-wide association studies (GWAS), is actively identifying new genetic markers. This work is vital for finding new avenues for investigation, which could lead to improved diagnostic tools, better ways to assess risk, and the development of more targeted therapies in the future.
10. Why do some people with mastocytosis have fewer symptoms?
The wide range of symptoms and disease severity, from mild cutaneous forms to more severe systemic forms, is a hallmark of mastocytosis. This variability is partly explained by constitutional genetic variations and the specific types of somatic mutations present, like KIT D816V. These genetic differences can influence how intensely the mast cells accumulate and affect your body, leading to fewer or more noticeable symptoms.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
[1] Galata, G. et al. "Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis." Am J Hum Genet, 2021.
[2] Nedoszytko, B. et al. "Results from a Genome-Wide Association Study (GWAS) in Mastocytosis Reveal New Gene Polymorphisms Associated with WHO Subgroups." Int J Mol Sci, 2020.
[3] Theoharides, T.C., et al. "Mast Cells, Mastocytosis, and Related Disorders." N. Engl. J. Med., vol. 373, no. 19, 2015, pp. 1885–1886.
[4] Orfao, A., A.C. Garcia-Montero, L. Sanchez, and L. Escribano. "Recent advances in the understanding of mastocytosis: The role of KIT mutations." Br. J. Haematol., vol. 138, 2007, pp. 12–30.
[5] Valent, P., et al. "Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts." Blood, vol. 129, no. 11, 2017, pp. 1420–1427.
[6] Rausz, E., et al. "Comparative analysis of IL6 and IL6 receptor gene polymorphisms in mastocytosis." Br. J. Haematol., vol. 160, 2013, pp. 216–219.
[7] Alvarez-Twose, I., et al. "Imatinib in systemic mastocytosis: A phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature." Oncotarget, vol. 8, 2017, pp. 68950–68963.
[8] Daley, T., D.D. Metcalfe, and C. Akin. "Association of the Q576R polymorphism in the interleukin-4 receptor alpha chain with indolent mastocytosis limited to the skin." Blood, vol. 98, 2001, pp. 880–882.
[9] Lange, M., et al. "Interleukin-31 Polymorphisms and Serum IL-31 Level in Patients with Mastocytosis: Correlation with Clinical Presentation and Pruritus." Acta Derm. Venereol., vol. 97, 2017, pp. 47–53.
[10] Nedoszytko, B., et al. "The Possible Role of Gene Variant Coding Nonfunctional Toll-Like Receptor 2 in the Pathogenesis of Mastocytosis." Int. Arch. Allergy Immunol., vol. 177, 2018, pp. 80–86.
[11] Traina, F., et al. "Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis." PLoS ONE, vol. 7, 2012, e43090.
[12] Davies, W., and K.D. Tew. "ATP-binding Cassette transporter-2 (ABCA2) as a Therapeutic Target." Biochem Pharmacol, vol. 151, 2018, pp. 188–200.