Cutaneous mastocytosis
Haematolymphoid Tumours (WHO Classification, 5th ed.)
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editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationThis page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Cutaneous Mastocytosis.
(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)
Primary Author(s)*
S. Shawn Liu, MD, PhD and Thuy Phung, MD, PhD
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Haematolymphoid Tumours (5th ed.) |
| Category | Myeloid proliferations and neoplasms |
| Family | Mastocytosis |
| Type | N/A |
| Subtype(s) | Cutaneous mastocytosis |
WHO Essential and Desirable Genetic Diagnostic Criteria
(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)
| WHO Essential Criteria (Genetics)* | |
| WHO Desirable Criteria (Genetics)* | |
| Other Classification |
*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.
Related Terminology
(Instructions: The table will have the related terminology from the WHO autocompleted.)
| Acceptable | |
| Not Recommended |
Gene Rearrangements
Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Driver Gene | Fusion(s) and Common Partner Genes | Molecular Pathogenesis | Typical Chromosomal Alteration(s) | Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE: ABL1 | EXAMPLE: BCR::ABL1 | EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1. | EXAMPLE: t(9;22)(q34;q11.2) | EXAMPLE: Common (CML) | EXAMPLE: D, P, T | EXAMPLE: Yes (WHO, NCCN) | EXAMPLE:
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference). |
| EXAMPLE: CIC | EXAMPLE: CIC::DUX4 | EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5. | EXAMPLE: t(4;19)(q25;q13) | EXAMPLE: Common (CIC-rearranged sarcoma) | EXAMPLE: D | EXAMPLE:
DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references). | |
| EXAMPLE: ALK | EXAMPLE: ELM4::ALK
|
EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18. | EXAMPLE: N/A | EXAMPLE: Rare (Lung adenocarcinoma) | EXAMPLE: T | EXAMPLE:
Both balanced and unbalanced forms are observed by FISH (add references). | |
| EXAMPLE: ABL1 | EXAMPLE: N/A | EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways. | EXAMPLE: N/A | EXAMPLE: Recurrent (IDH-wildtype Glioblastoma) | EXAMPLE: D, P, T | ||
Individual Region Genomic Gain/Loss/LOH
Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)
| Chr # | Gain, Loss, Amp, LOH | Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] | Relevant Gene(s) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| EXAMPLE:
7 |
EXAMPLE: Loss | EXAMPLE:
chr7 |
EXAMPLE:
Unknown |
EXAMPLE: D, P | EXAMPLE: No | EXAMPLE:
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references). |
| EXAMPLE:
8 |
EXAMPLE: Gain | EXAMPLE:
chr8 |
EXAMPLE:
Unknown |
EXAMPLE: D, P | EXAMPLE:
Common recurrent secondary finding for t(8;21) (add references). | |
| EXAMPLE:
17 |
EXAMPLE: Amp | EXAMPLE:
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb] |
EXAMPLE:
ERBB2 |
EXAMPLE: D, P, T | EXAMPLE:
Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined. | |
Characteristic Chromosomal or Other Global Mutational Patterns
Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Chromosomal Pattern | Molecular Pathogenesis | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|
| EXAMPLE:
Co-deletion of 1p and 18q |
EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). | EXAMPLE: Common (Oligodendroglioma) | EXAMPLE: D, P | ||
| EXAMPLE:
Microsatellite instability - hypermutated |
EXAMPLE: Common (Endometrial carcinoma) | EXAMPLE: P, T | |||
Gene Mutations (SNV/INDEL)
Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Gene | Genetic Alteration | Tumor Suppressor Gene, Oncogene, Other | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| EXAMPLE:EGFR
|
EXAMPLE: Exon 18-21 activating mutations | EXAMPLE: Oncogene | EXAMPLE: Common (lung cancer) | EXAMPLE: T | EXAMPLE: Yes (NCCN) | EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references). |
| EXAMPLE: TP53; Variable LOF mutations
|
EXAMPLE: Variable LOF mutations | EXAMPLE: Tumor Supressor Gene | EXAMPLE: Common (breast cancer) | EXAMPLE: P | EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer. | |
| EXAMPLE: BRAF; Activating mutations | EXAMPLE: Activating mutations | EXAMPLE: Oncogene | EXAMPLE: Common (melanoma) | EXAMPLE: T | ||
Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
editv4:Gene Mutations (SNV/INDEL)The content below was from the old template. Please incorporate above.
Put your text here and/or fill in the tables
| Gene | Mutation | Oncogene/Tumor Suppressor/Other | Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) | Prevalence (COSMIC/TCGA/Other) |
|---|---|---|---|---|
| c-KIT | c.2447A>T; p.D816V
(Chr 4: 54733154-54733155) |
Oncogene | GOF | 40-80%[1][2] |
| c-KIT[1][3] [4] | c.2446G>T; p.D816Y (Chr 4: 54733153-54733154) | Oncogene | GOF | |
| c-KIT[1] | c.2446_2447delinsAT; p.D816I (Chr 4: 54733153-54733155) | Oncogene | GOF | |
| c-KIT[1] | c.1715A>C; p.D572A (Chr 4: 54727482-54727483) | Oncogene | GOF | |
| c-KIT[1] | c.1526A>T; p.K509I (Chr 4: 54726035-54726036) | Oncogene | LOF | |
| c-KIT[1] | c.1621A>C; p.M541L (Chr 4: 54727297-54727298) | Oncogene | LOF | |
| c-KIT[1] | c.1328G>A; p.C443Y (Chr 4: 54723679-54723680) | Oncogene | LOF | |
| c-KIT[1] | c.1427G>T; p.S476I (Chr 4: 54725936-54725937) | Oncogene | LOF | |
| c-KIT[1] | c.1255_1257del; p.D419del (Chr 4: 54723606-54723609) | Oncogene | ||
| c-KIT[1] | c.1249_1255delinsT; p.T417_D419delinsY (Chr 4: 54723601-54723607) | Oncogene | LOF | |
| c-KIT[1] | c.1255insTTCTTC; p.D419insFF (Chr 4: 54723606-54723607) | Oncogene | ||
| c-KIT[1] | c.1500_1505dup; p.S501‐A502dup (Chr 4: 54726014-54726016) | Oncogene | ||
| c-KIT[1] | ITD AY502‐503 | Oncogene | LOF | |
| c-KIT[1] | ITD NFAF505‐508 | Oncogene | ||
| c-KIT | D815K | Oncogene | <5% [4] | |
| c-KIT[3] | E839K | Oncogene | LOF | |
| c-KIT | c.2446_2447delincTT; p.D816F (Chr 4: 54733153-54733155) | Oncogene | GOF | <5%[3][4] |
| c-KIT | c.2446_2448delinsCAT; p.D816H (Chr 4: 54733153-54733156) | Oncogene | GOF | <5% [5] |
| c-KIT | c.2459A>G; p.D820G (Chr 4: 54733166-54733167) | Oncogene | <5% [6] | |
| c-KIT | c.2449A>G; p.I817V (Chr 4: 54733156-54733157) | Oncogene | <5% [7] | |
| c-KIT | c.2446_2447insTCATAG; p.R815_D816insVI (Chr 4: 54733153-54733155) | Oncogene | <5% [7] | |
| c-KIT | c.1598C>A; p.A533D (Chr 4: 54727274-54727275) | Oncogene | Germline | <5% [8] |
| c-KIT | F522C | Oncogene | Germline | <5% [9] |
| c-KIT | Y560G | Oncogene | <5%[10] | |
| TET2 [11] | 1777_1778insG | Suppressor | ||
| TET2[11] | 723_724delAG | Suppressor | ||
| TET2[11] | 3248_delT | Suppressor | ||
| TET2[11] | 278_279insA | Suppressor | ||
| TET2[11] | 1554_delG | Suppressor | ||
| TET2[11] | 1305A>G | Suppressor | ||
| TET2[11] | 2628C>T | Suppressor | ||
| TET2[11] | 231C>T | Suppressor | ||
| TET2[11] | 695_696insT | Suppressor | ||
| TET2[11] | 3070_3071insA | Suppressor | ||
| TET2[11] | 955-956insT | Suppressor | ||
| TET2[11] | 2812-2813insT | Suppressor | ||
| TET2[11] | 252_262delCTCTACAGAAG | Suppressor | ||
| TET2[11] | 236_delG | Suppressor | ||
| TET2[11] | 2468_2469insA | Suppressor | ||
| TET2[11] | 208C>T | Suppressor | ||
| NRAS[12] | c.35G>A; p.G12D (Chr 1: 114716125-114716126) | Oncogene | ||
| NRAS[12] | c.38G>A; p.G13D (Chr 1: 114716122-114716123) | Oncogene |
Other Mutations
| Type | Gene/Region/Other |
|---|---|
| Concomitant Mutations | EXAMPLE: IDH1 R123H |
| Secondary Mutations | EXAMPLE: Trisomy 7 |
| Mutually Exclusive | EXAMPLE: EGFR Amplification |
End of V4 Section
Epigenomic Alterations
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Genes and Main Pathways Involved
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| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| EXAMPLE: BRAF and MAP2K1; Activating mutations | EXAMPLE: MAPK signaling | EXAMPLE: Increased cell growth and proliferation |
| EXAMPLE: CDKN2A; Inactivating mutations | EXAMPLE: Cell cycle regulation | EXAMPLE: Unregulated cell division |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
Genetic Diagnostic Testing Methods
Put your text here (Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.)
Familial Forms
c-KIT A533D [8]
c-KIT F522C [9]
Additional Information
Put your text here
Links
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References
(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)
- ↑ Jump up to: 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 Bodemer, Christine; et al. (2010-03). "Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations". The Journal of Investigative Dermatology. 130 (3): 804–815. doi:10.1038/jid.2009.281. ISSN 1523-1747. PMID 19865100. Check date values in:
|date=(help) - ↑ Longley, B. J.; et al. (2001-07). "Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy". Leukemia Research. 25 (7): 571–576. doi:10.1016/s0145-2126(01)00028-5. ISSN 0145-2126. PMID 11377682. Check date values in:
|date=(help) - ↑ Jump up to: 3.0 3.1 3.2 Longley, B. J.; et al. (1999-02-16). "Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis". Proceedings of the National Academy of Sciences of the United States of America. 96 (4): 1609–1614. doi:10.1073/pnas.96.4.1609. ISSN 0027-8424. PMC 15534. PMID 9990072.CS1 maint: PMC format (link)
- ↑ Jump up to: 4.0 4.1 4.2 Sotlar, Karl; et al. (2003-03). "One-step detection of c-kit point mutations using peptide nucleic acid-mediated polymerase chain reaction clamping and hybridization probes". The American Journal of Pathology. 162 (3): 737–746. doi:10.1016/S0002-9440(10)63870-9. ISSN 0002-9440. PMC 1868096. PMID 12598308. Check date values in:
|date=(help) - ↑ Pullarkat, V. A.; et al. (2000-12). "Mast cell disease associated with acute myeloid leukemia: detection of a new c-kit mutation Asp816His". American Journal of Hematology. 65 (4): 307–309. doi:10.1002/1096-8652(200012)65:43.0.co;2-f. ISSN 0361-8609. PMID 11074560. Check date values in:
|date=(help) - ↑ Pignon, J. M.; et al. (1997-02). "A new c-kit mutation in a case of aggressive mast cell disease". British Journal of Haematology. 96 (2): 374–376. doi:10.1046/j.1365-2141.1997.d01-2042.x. ISSN 0007-1048. PMID 9029028. Check date values in:
|date=(help) - ↑ Jump up to: 7.0 7.1 Garcia-Montero, Andres C.; et al. (2006-10-01). "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. 108 (7): 2366–2372. doi:10.1182/blood-2006-04-015545. ISSN 0006-4971. PMID 16741248.
- ↑ Jump up to: 8.0 8.1 Tang, X.; et al. (2004-06). "A germline mutation in KIT in familial diffuse cutaneous mastocytosis". Journal of Medical Genetics. 41 (6): e88. doi:10.1136/jmg.2003.015156. ISSN 1468-6244. PMC 1735799. PMID 15173254. Check date values in:
|date=(help) - ↑ Jump up to: 9.0 9.1 Akin, Cem; et al. (2004-04-15). "A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib". Blood. 103 (8): 3222–3225. doi:10.1182/blood-2003-11-3816. ISSN 0006-4971. PMID 15070706.
- ↑ Lim, Ken-Hong; et al. (2009-06-04). "Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors". Blood. 113 (23): 5727–5736. doi:10.1182/blood-2009-02-205237. ISSN 1528-0020. PMID 19363219.
- ↑ Jump up to: 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 11.12 11.13 11.14 11.15 Tefferi, A.; et al. (2009-05). "Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates". Leukemia. 23 (5): 900–904. doi:10.1038/leu.2009.37. ISSN 1476-5551. PMC 4654631. PMID 19262599. Check date values in:
|date=(help) - ↑ Jump up to: 12.0 12.1 Wilson, Todd M.; et al. (2011-03). "Clonal analysis of NRAS activating mutations in KIT-D816V systemic mastocytosis". Haematologica. 96 (3): 459–463. doi:10.3324/haematol.2010.031690. ISSN 1592-8721. PMC 3046279. PMID 21134978. Check date values in:
|date=(help)
Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative. When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
Prior Author(s):
*Citation of this Page: “Cutaneous mastocytosis”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/11/2025, https://ccga.io/index.php/HAEM5:Cutaneous_mastocytosis.