KIT Mutant Melanoma

MONDO:0003865 Pathograph 6 melanoma

KIT-mutant melanoma is a molecular subtype occurring predominantly in acral, mucosal, and chronically sun-damaged melanomas, characterized by activating mutations or amplifications of the KIT receptor tyrosine kinase gene. KIT mutations occur in approximately 15-20% of acral melanomas, 20-35% of mucosal melanomas, and 15-20% of melanomas arising on chronically sun-damaged skin, but are rare in common cutaneous melanomas. KIT signaling activates both MAPK and PI3K pathways, driving melanocyte proliferation and survival. KIT-mutant melanoma can be treated with imatinib and other KIT inhibitors, though responses are variable depending on mutation type, with exon 11 and 13 mutations showing better responses than amplification alone.

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Mappings

Definitions

Inheritance

Differentials

Datasets

Trials

Models

References

Deep Research

🏷

Classifications

Harrison's Chapter

ICD-O Morphology

◆

Subtypes

Acral KIT-Mutant Melanoma

Melanoma arising on acral surfaces (palms, soles, subungual regions) with KIT mutation. Represents the most common anatomic site for KIT-mutant melanoma. Not associated with sun exposure.

Mucosal KIT-Mutant Melanoma

Melanoma arising from mucosal surfaces (oral, nasal, genital, anorectal) with KIT mutation. Associated with poor prognosis due to delayed diagnosis and limited surgical options.

Chronically Sun-Damaged KIT-Mutant Melanoma

Melanoma arising on chronically sun-damaged skin with KIT mutation or copy number increase. Curtin et al. identified KIT alterations in 28% of melanomas on chronically sun-damaged skin.

⚙

Pathophysiology

KIT Receptor Tyrosine Kinase Activation

KIT mutations, most commonly in exons 11, 13, and 17, result in constitutive receptor activation independent of stem cell factor (SCF) ligand binding. Mutations may cause ligand-independent dimerization, altered kinase domain conformation, or loss of autoinhibitory mechanisms, leading to persistent downstream signaling.

melanocyte link

signal transduction link ↑ INCREASED

Downstream

MAPK Pathway Activation KIT signals through RAS to activate RAF-MEK-ERK cascade

PI3K-AKT Pathway Activation KIT directly activates PI3K through phosphorylation of adapter proteins

JAK-STAT Pathway Activation KIT signaling also engages JAK-STAT transcriptional programs.

Show evidence (4 references)

PMID:41042158 PARTIAL

"Mutation of c-KIT has been observed in acral, mucosal, and chronically sun-damaged melanoma subtypes marking it as a key therapeutic target for melanoma."

This abstract documents c-KIT mutations in melanoma subtypes associated with KIT-mutant disease.

PMID:16908931 SUPPORT Human Clinical

"mutations and/or copy number increases of KIT in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage"

Seminal study by Curtin et al. quantifying KIT mutation frequency across melanoma subtypes, establishing KIT as an oncogene in acral, mucosal, and CSD melanomas.

PMID:22453014 SUPPORT Human Clinical

"Activating mutations in KIT have been discovered in a significant proportion of melanomas arising from acral, mucosal, and chronically sun-damaged sites and represent an important melanoma genetic subset."

Review confirming KIT mutations as a distinct genetic subset in melanoma.

+ 1 more reference

MAPK Pathway Activation

Activated KIT recruits adapter proteins that engage RAS-MAPK signaling, driving melanocyte proliferation through ERK-mediated transcriptional programs promoting cell cycle progression.

MAPK cascade link ↑ INCREASED

Downstream

Uncontrolled Melanocyte Proliferation ERK activation drives cyclin D1 expression and cell cycle entry

Show evidence (1 reference)

PMID:19047099 SUPPORT In Vitro

"Exposure to drug affected the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT, JAK-STAT, and antiapoptotic pathways."

In vitro study demonstrating that KIT inhibition affects the MAPK pathway in melanoma cells, confirming KIT signals through MAPK.

PI3K-AKT Pathway Activation

KIT activates PI3K through recruitment and phosphorylation of adapter proteins. Subsequent AKT activation promotes cell survival through inhibition of pro-apoptotic proteins and activation of mTOR signaling.

signal transduction link ↑ INCREASED

Downstream

Cell Survival and Anti-Apoptosis AKT phosphorylates and inactivates pro-apoptotic factors

Show evidence (1 reference)

PMID:19047099 SUPPORT In Vitro

"Exposure to drug affected the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT, JAK-STAT, and antiapoptotic pathways."

In vitro study demonstrating that KIT inhibition affects the PI3K/AKT pathway in melanoma cells.

JAK-STAT Pathway Activation

KIT-mutant melanoma cells also show JAK-STAT pathway modulation downstream of KIT kinase activity, supporting transcriptional programs that complement MAPK and PI3K-AKT signaling.

JAK-STAT signaling pathway link ↑ INCREASED

Downstream

Uncontrolled Melanocyte Proliferation JAK-STAT signaling contributes to KIT-driven transcriptional programs.

Show evidence (1 reference)

PMID:19047099 SUPPORT In Vitro

"Exposure to drug affected the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT, JAK-STAT, and antiapoptotic pathways."

In vitro KIT-mutant melanoma data show that KIT inhibition affects JAK-STAT alongside MAPK, PI3K/AKT, and antiapoptotic pathways.

Uncontrolled Melanocyte Proliferation

Constitutive KIT signaling through MAPK and PI3K pathways drives abnormal melanocyte proliferation in acral and mucosal sites, leading to tumor formation.

melanocyte link

cell population proliferation link ↑ INCREASED

Show evidence (1 reference)

PMID:19047099 SUPPORT In Vitro

"Imatinib dramatically decreased proliferation and was cytotoxic to a KIT mutated and amplified cell culture."

Demonstrates that KIT drives melanoma cell proliferation, as inhibition with imatinib dramatically decreased proliferation.

Cell Survival and Anti-Apoptosis

PI3K-AKT activation downstream of KIT promotes melanoma cell survival through phosphorylation-mediated inactivation of pro-apoptotic proteins and activation of survival pathways.

apoptotic process link ↓ DECREASED

Show evidence (1 reference)

PMID:19047099 SUPPORT In Vitro

"In vitro analyses revealed major sensitivity to KIT kinase inhibition by imatinib, with potent induction of melanoma cell apoptosis."

Demonstrates that KIT signaling suppresses apoptosis in melanoma cells, as KIT inhibition potently induced apoptosis.

✶

Histopathology

Melanocytic Neoplasm VERY_FREQUENT

Malignant melanoma represents a neoplasm stemming from melanocytes.

Show evidence (1 reference)

PMID:27268913 PARTIAL

"Malignant melanoma represents a neoplasm stemming from melanocytes"

Abstract defines melanoma as a neoplasm stemming from melanocytes.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Integument 2

Acral Lentiginous Melanoma FREQUENT Acral lentiginous melanoma (HP:0012060)

Show evidence (1 reference)

PMID:16908931 SUPPORT Human Clinical

"mutations and/or copy number increases of KIT in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage"

Curtin et al. established that 36% of acral melanomas harbor KIT alterations.

Cutaneous Melanoma FREQUENT Cutaneous melanoma (HP:0012056)

Other 2

Melanoma Melanoma (HP:0002861)

Show evidence (1 reference)

PMID:16908931 SUPPORT Human Clinical

"KIT is an important oncogene in melanoma."

Curtin et al. established KIT as an oncogene driving melanoma in specific subtypes.

Lentigo Maligna Melanoma OCCASIONAL Lentigo maligna melanoma (HP:0012059)

Show evidence (1 reference)

PMID:16908931 SUPPORT Human Clinical

"mutations and/or copy number increases of KIT in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage"

Curtin et al. established that 28% of melanomas on chronically sun-damaged skin harbor KIT alterations, supporting this phenotype entry.

🧬

Genetic Associations

KIT Exon 11 Mutations (Somatic Oncogenic Mutation)

Show evidence (1 reference)

PMID:21642685 SUPPORT Human Clinical

"all 6 responses occurred in tumors with L576P or K642E mutations, the most common mutations in melanoma"

Carvajal et al. showed that responses to imatinib occurred in tumors with L576P (exon 11) and K642E (exon 13) mutations.

KIT Exon 13 Mutations (K642E) (Somatic Oncogenic Mutation)

Show evidence (1 reference)

PMID:19035443 SUPPORT Human Clinical

"Sequence analysis revealed K642E and D820Y mutations in two metastases."

Confirms K642E as a recurrent KIT mutation found in acral and mucosal melanoma metastases.

KIT Exon 17 Mutations (D820Y) (Somatic Oncogenic Mutation)

KIT Amplification (Somatic Alteration)

Show evidence (1 reference)

PMID:23775962 SUPPORT Human Clinical

"BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only)."

Directly demonstrates poorer imatinib response for KIT amplification-only tumors compared with KIT-mutated tumors.

💊

Treatments

Imatinib

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: imatinib ↗

Tyrosine kinase inhibitor with activity against KIT, ABL, and PDGFR. Shows clinical benefit in KIT-mutant melanoma, particularly for exon 11 and 13 mutations. Response rates of approximately 16-29% with meaningful disease stabilization in additional patients.

Show evidence (3 references)

PMID:23775962 SUPPORT Human Clinical

"Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%."

Phase II trial reports response rates to imatinib in KIT-altered melanoma.

PMID:21642685 SUPPORT Human Clinical

"The overall durable response rate was 16%"

Phase II trial by Carvajal et al. demonstrating a 16% durable response rate to imatinib in KIT-mutant melanoma patients.

PMID:34562816 SUPPORT Human Clinical

"The pooled ORR for all inhibitors was 15%"

Meta-analysis of 19 studies (601 patients) pooling response rates across KIT inhibitors in KIT-mutant melanoma.

Nilotinib

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: nilotinib ↗

Second-generation KIT inhibitor with increased potency compared to imatinib. May have activity in some imatinib-resistant cases depending on the specific mutation conferring resistance. Meta-analysis showed highest pooled ORR of 20% among KIT inhibitors.

Show evidence (1 reference)

PMID:34562816 SUPPORT Human Clinical

"Subgroup analysis revealed the highest ORR (20%; 95% CI: 14-26%) for nilotinib."

Meta-analysis showing nilotinib had the highest objective response rate among KIT inhibitors tested.

Dasatinib

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: dasatinib ↗

Multi-kinase inhibitor with activity against KIT, ABL, and SRC family kinases. Phase II trial showed limited response rate in KIT-mutant melanoma, and imatinib remains the KIT inhibitor of choice.

Show evidence (1 reference)

PMID:28334439 PARTIAL Human Clinical

"it is recommended that imatinib remain the KIT tyrosine kinase inhibitor of choice for unresectable KIT+ melanoma"

Phase II trial showing low dasatinib response rate in KIT-mutant melanoma, recommending imatinib as the preferred agent.

Ripretinib

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: ripretinib

Broad-spectrum KIT/PDGFRA switch-control tyrosine kinase inhibitor studied in KIT-altered metastatic melanoma. Phase I expansion data showed a 23% confirmed objective response rate and median progression-free survival of 7.3 months.

Show evidence (2 references)

PMID:35753087 SUPPORT Human Clinical

"Confirmed objective response rate (ORR) was 23%"

Phase I expansion data support ripretinib objective responses in KIT-altered metastatic melanoma.

PMID:35753087 SUPPORT Human Clinical

"Median progression-free survival (mPFS) was 7.3 months (95% CI 1.9-13.6 months)."

Phase I expansion data support a median PFS of 7.3 months with ripretinib in KIT-altered metastatic melanoma.

Immune Checkpoint Inhibitors

Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262

Anti-PD-1 antibodies (pembrolizumab, nivolumab) are also used in KIT-mutant melanoma. The optimal sequencing of KIT inhibitors versus immunotherapy depends on mutation status and patient characteristics.

{ }

Source YAML

click to show

name: KIT Mutant Melanoma
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-05-03T00:00:00Z'
description: >-
  KIT-mutant melanoma is a molecular subtype occurring predominantly in acral,
  mucosal, and chronically sun-damaged melanomas, characterized by activating
  mutations or amplifications of the KIT receptor tyrosine kinase gene. KIT
  mutations occur in approximately 15-20% of acral melanomas, 20-35% of mucosal
  melanomas, and 15-20% of melanomas arising on chronically sun-damaged skin,
  but are rare in common cutaneous melanomas. KIT signaling activates both MAPK
  and PI3K pathways, driving melanocyte proliferation and survival. KIT-mutant
  melanoma can be treated with imatinib and other KIT inhibitors, though responses
  are variable depending on mutation type, with exon 11 and 13 mutations showing
  better responses than amplification alone.
categories:
- Skin Cancer
- Molecularly Defined Cancer
- Oncogene-Driven Cancer
parents:
- melanoma
has_subtypes:
- name: Acral KIT-Mutant Melanoma
  description: >-
    Melanoma arising on acral surfaces (palms, soles, subungual regions) with
    KIT mutation. Represents the most common anatomic site for KIT-mutant
    melanoma. Not associated with sun exposure.
- name: Mucosal KIT-Mutant Melanoma
  description: >-
    Melanoma arising from mucosal surfaces (oral, nasal, genital, anorectal)
    with KIT mutation. Associated with poor prognosis due to delayed diagnosis
    and limited surgical options.
- name: Chronically Sun-Damaged KIT-Mutant Melanoma
  description: >-
    Melanoma arising on chronically sun-damaged skin with KIT mutation or copy
    number increase. Curtin et al. identified KIT alterations in 28% of
    melanomas on chronically sun-damaged skin.
pathophysiology:
- name: KIT Receptor Tyrosine Kinase Activation
  description: >-
    KIT mutations, most commonly in exons 11, 13, and 17, result in constitutive
    receptor activation independent of stem cell factor (SCF) ligand binding.
    Mutations may cause ligand-independent dimerization, altered kinase domain
    conformation, or loss of autoinhibitory mechanisms, leading to persistent
    downstream signaling.
  evidence:
  - reference: PMID:41042158
    reference_title: "c-KIT Small Molecule Inhibitors as a Therapeutic Strategy for Melanoma: Clinical Insights, SAR, and Future Directions."
    supports: PARTIAL
    snippet: Mutation of c-KIT has been observed in acral, mucosal, and chronically sun-damaged melanoma subtypes marking it as a key therapeutic target for melanoma.
    explanation: This abstract documents c-KIT mutations in melanoma subtypes associated with KIT-mutant disease.
  - reference: PMID:16908931
    reference_title: Somatic activation of KIT in distinct subtypes of melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mutations and/or copy number increases of KIT in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage"
    explanation: Seminal study by Curtin et al. quantifying KIT mutation frequency across melanoma subtypes, establishing KIT as an oncogene in acral, mucosal, and CSD melanomas.
  - reference: PMID:22453014
    reference_title: Therapeutic implications of KIT in melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Activating mutations in KIT have been discovered in a significant proportion of melanomas arising from acral, mucosal, and chronically sun-damaged sites and represent an important melanoma genetic subset."
    explanation: Review confirming KIT mutations as a distinct genetic subset in melanoma.
  - reference: PMID:19035443
    reference_title: Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Western blot analysis showed phosphorylation of the KIT receptor in 8 (62%) of 13 cryopreserved samples, indicating the frequent pathological activation of the receptor in vivo."
    explanation: Demonstrates frequent constitutive KIT activation in acral and mucosal melanoma metastases.
  cell_types:
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  biological_processes:
  - preferred_term: signal transduction
    modifier: INCREASED
    term:
      id: GO:0007165
      label: signal transduction
  downstream:
  - target: MAPK Pathway Activation
    description: KIT signals through RAS to activate RAF-MEK-ERK cascade
  - target: PI3K-AKT Pathway Activation
    description: KIT directly activates PI3K through phosphorylation of adapter proteins
  - target: JAK-STAT Pathway Activation
    description: KIT signaling also engages JAK-STAT transcriptional programs.
- name: MAPK Pathway Activation
  description: >-
    Activated KIT recruits adapter proteins that engage RAS-MAPK signaling,
    driving melanocyte proliferation through ERK-mediated transcriptional
    programs promoting cell cycle progression.
  evidence:
  - reference: PMID:19047099
    reference_title: Imatinib targeting of KIT-mutant oncoprotein in melanoma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Exposure to drug affected the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT, JAK-STAT, and antiapoptotic pathways."
    explanation: In vitro study demonstrating that KIT inhibition affects the MAPK pathway in melanoma cells, confirming KIT signals through MAPK.
  biological_processes:
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  downstream:
  - target: Uncontrolled Melanocyte Proliferation
    description: ERK activation drives cyclin D1 expression and cell cycle entry
- name: PI3K-AKT Pathway Activation
  description: >-
    KIT activates PI3K through recruitment and phosphorylation of adapter
    proteins. Subsequent AKT activation promotes cell survival through
    inhibition of pro-apoptotic proteins and activation of mTOR signaling.
  evidence:
  - reference: PMID:19047099
    reference_title: Imatinib targeting of KIT-mutant oncoprotein in melanoma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Exposure to drug affected the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT, JAK-STAT, and antiapoptotic pathways."
    explanation: In vitro study demonstrating that KIT inhibition affects the PI3K/AKT pathway in melanoma cells.
  biological_processes:
  - preferred_term: signal transduction
    modifier: INCREASED
    term:
      id: GO:0007165
      label: signal transduction
  downstream:
  - target: Cell Survival and Anti-Apoptosis
    description: AKT phosphorylates and inactivates pro-apoptotic factors
- name: JAK-STAT Pathway Activation
  description: >-
    KIT-mutant melanoma cells also show JAK-STAT pathway modulation downstream
    of KIT kinase activity, supporting transcriptional programs that complement
    MAPK and PI3K-AKT signaling.
  evidence:
  - reference: PMID:19047099
    reference_title: Imatinib targeting of KIT-mutant oncoprotein in melanoma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Exposure to drug affected the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT, JAK-STAT, and antiapoptotic pathways."
    explanation: In vitro KIT-mutant melanoma data show that KIT inhibition affects JAK-STAT alongside MAPK, PI3K/AKT, and antiapoptotic pathways.
  biological_processes:
  - preferred_term: JAK-STAT signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
  downstream:
  - target: Uncontrolled Melanocyte Proliferation
    description: JAK-STAT signaling contributes to KIT-driven transcriptional programs.
- name: Uncontrolled Melanocyte Proliferation
  description: >-
    Constitutive KIT signaling through MAPK and PI3K pathways drives abnormal
    melanocyte proliferation in acral and mucosal sites, leading to tumor formation.
  evidence:
  - reference: PMID:19047099
    reference_title: Imatinib targeting of KIT-mutant oncoprotein in melanoma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Imatinib dramatically decreased proliferation and was cytotoxic to a KIT mutated and amplified cell culture."
    explanation: Demonstrates that KIT drives melanoma cell proliferation, as inhibition with imatinib dramatically decreased proliferation.
  cell_types:
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
- name: Cell Survival and Anti-Apoptosis
  description: >-
    PI3K-AKT activation downstream of KIT promotes melanoma cell survival
    through phosphorylation-mediated inactivation of pro-apoptotic proteins
    and activation of survival pathways.
  evidence:
  - reference: PMID:19047099
    reference_title: Imatinib targeting of KIT-mutant oncoprotein in melanoma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro analyses revealed major sensitivity to KIT kinase inhibition by imatinib, with potent induction of melanoma cell apoptosis."
    explanation: Demonstrates that KIT signaling suppresses apoptosis in melanoma cells, as KIT inhibition potently induced apoptosis.
  biological_processes:
  - preferred_term: apoptotic process
    modifier: DECREASED
    term:
      id: GO:0006915
      label: apoptotic process
histopathology:
- name: Melanocytic Neoplasm
  finding_term:
    preferred_term: Melanocytic Neoplasm
    term:
      id: NCIT:C7058
      label: Melanocytic Neoplasm
  frequency: VERY_FREQUENT
  description: Malignant melanoma represents a neoplasm stemming from melanocytes.
  evidence:
  - reference: PMID:27268913
    reference_title: "Malignant melanoma: diagnosis, treatment and cancer stem cells."
    supports: PARTIAL
    snippet: "Malignant melanoma represents a neoplasm stemming from melanocytes"
    explanation: Abstract defines melanoma as a neoplasm stemming from melanocytes.

phenotypes:
- category: Dermatologic
  name: Acral Lentiginous Melanoma
  frequency: FREQUENT
  diagnostic: true
  description: >-
    Melanoma arising on acral surfaces including palms, soles, and nail beds.
    Presents as pigmented macule with irregular borders, often diagnosed at
    advanced stage due to location. KIT mutations are found in approximately
    36% of acral melanomas.
  evidence:
  - reference: PMID:16908931
    reference_title: Somatic activation of KIT in distinct subtypes of melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mutations and/or copy number increases of KIT in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage"
    explanation: Curtin et al. established that 36% of acral melanomas harbor KIT alterations.
  phenotype_term:
    preferred_term: Acral lentiginous melanoma
    term:
      id: HP:0012060
      label: Acral lentiginous melanoma
- category: Dermatologic
  name: Cutaneous Melanoma
  frequency: FREQUENT
  description: >-
    Melanoma arising on chronically sun-damaged skin may also harbor KIT mutations,
    though less commonly than acral or mucosal sites.
  phenotype_term:
    preferred_term: Cutaneous melanoma
    term:
      id: HP:0012056
      label: Cutaneous melanoma
- category: Dermatologic
  name: Melanoma
  description: >-
    KIT-mutant melanoma is a molecular subtype of melanoma characterized by
    activating mutations or amplification of the KIT gene. It occurs predominantly
    in acral, mucosal, and chronically sun-damaged sites rather than
    intermittently sun-exposed skin.
  evidence:
  - reference: PMID:16908931
    reference_title: Somatic activation of KIT in distinct subtypes of melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KIT is an important oncogene in melanoma."
    explanation: Curtin et al. established KIT as an oncogene driving melanoma in specific subtypes.
  phenotype_term:
    preferred_term: Melanoma
    term:
      id: HP:0002861
      label: Melanoma
- category: Dermatologic
  name: Lentigo Maligna Melanoma
  frequency: OCCASIONAL
  description: >-
    Melanoma arising in chronically sun-damaged skin, particularly head and neck
    regions. KIT mutations are found in approximately 28% of melanomas on
    chronically sun-damaged skin.
  phenotype_term:
    preferred_term: Lentigo maligna melanoma
    term:
      id: HP:0012059
      label: Lentigo maligna melanoma
  evidence:
  - reference: PMID:16908931
    reference_title: Somatic activation of KIT in distinct subtypes of melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mutations and/or copy number increases of KIT in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage"
    explanation: Curtin et al. established that 28% of melanomas on chronically sun-damaged skin harbor KIT alterations, supporting this phenotype entry.
genetic:
- name: KIT Exon 11 Mutations
  association: Somatic Oncogenic Mutation
  notes: >-
    Mutations in the juxtamembrane domain encoded by exon 11 disrupt autoinhibitory
    function, leading to constitutive receptor activation. These mutations typically
    show good response to imatinib therapy.
  evidence:
  - reference: PMID:21642685
    reference_title: KIT as a therapeutic target in metastatic melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all 6 responses occurred in tumors with L576P or K642E mutations, the most common mutations in melanoma"
    explanation: Carvajal et al. showed that responses to imatinib occurred in tumors with L576P (exon 11) and K642E (exon 13) mutations.
- name: KIT Exon 13 Mutations (K642E)
  association: Somatic Oncogenic Mutation
  notes: >-
    Point mutations in the kinase domain affecting the ATP-binding pocket. K642E
    is the most common exon 13 mutation and is sensitive to imatinib.
  evidence:
  - reference: PMID:19035443
    reference_title: Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence analysis revealed K642E and D820Y mutations in two metastases."
    explanation: Confirms K642E as a recurrent KIT mutation found in acral and mucosal melanoma metastases.
- name: KIT Exon 17 Mutations (D820Y)
  association: Somatic Oncogenic Mutation
  notes: >-
    Mutations in the activation loop of the kinase domain. Some exon 17 mutations,
    particularly D816V, confer resistance to imatinib but may respond to other
    KIT inhibitors.
- name: KIT Amplification
  association: Somatic Alteration
  notes: >-
    Gene amplification without mutation occurs in some acral and mucosal melanomas.
    Response to KIT inhibitors is generally poorer for amplification compared to
    activating point mutations.
  evidence:
  - reference: PMID:23775962
    reference_title: "Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only)."
    explanation: Directly demonstrates poorer imatinib response for KIT amplification-only tumors compared with KIT-mutated tumors.
treatments:
- name: Imatinib
  description: >-
    Tyrosine kinase inhibitor with activity against KIT, ABL, and PDGFR. Shows
    clinical benefit in KIT-mutant melanoma, particularly for exon 11 and 13
    mutations. Response rates of approximately 16-29% with meaningful disease
    stabilization in additional patients.
  evidence:
  - reference: PMID:23775962
    reference_title: "Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%."
    explanation: "Phase II trial reports response rates to imatinib in KIT-altered melanoma."
  - reference: PMID:21642685
    reference_title: KIT as a therapeutic target in metastatic melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall durable response rate was 16%"
    explanation: Phase II trial by Carvajal et al. demonstrating a 16% durable response rate to imatinib in KIT-mutant melanoma patients.
  - reference: PMID:34562816
    reference_title: "c-Kit inhibitors for unresectable or metastatic mucosal, acral or chronically sun-damaged melanoma: a systematic review and one-arm meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pooled ORR for all inhibitors was 15%"
    explanation: Meta-analysis of 19 studies (601 patients) pooling response rates across KIT inhibitors in KIT-mutant melanoma.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: imatinib
      term:
        id: CHEBI:45783
        label: imatinib
- name: Nilotinib
  description: >-
    Second-generation KIT inhibitor with increased potency compared to imatinib.
    May have activity in some imatinib-resistant cases depending on the specific
    mutation conferring resistance. Meta-analysis showed highest pooled ORR of
    20% among KIT inhibitors.
  evidence:
  - reference: PMID:34562816
    reference_title: "c-Kit inhibitors for unresectable or metastatic mucosal, acral or chronically sun-damaged melanoma: a systematic review and one-arm meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subgroup analysis revealed the highest ORR (20%; 95% CI: 14-26%) for nilotinib."
    explanation: Meta-analysis showing nilotinib had the highest objective response rate among KIT inhibitors tested.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: nilotinib
      term:
        id: CHEBI:52172
        label: nilotinib
- name: Dasatinib
  description: >-
    Multi-kinase inhibitor with activity against KIT, ABL, and SRC family kinases.
    Phase II trial showed limited response rate in KIT-mutant melanoma, and
    imatinib remains the KIT inhibitor of choice.
  evidence:
  - reference: PMID:28334439
    reference_title: "A phase 2 trial of dasatinib in patients with locally advanced or stage IV mucosal, acral, or vulvovaginal melanoma: A trial of the ECOG-ACRIN Cancer Research Group (E2607)."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "it is recommended that imatinib remain the KIT tyrosine kinase inhibitor of choice for unresectable KIT+ melanoma"
    explanation: Phase II trial showing low dasatinib response rate in KIT-mutant melanoma, recommending imatinib as the preferred agent.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: dasatinib
      term:
        id: CHEBI:49375
        label: dasatinib (anhydrous)
- name: Ripretinib
  description: >-
    Broad-spectrum KIT/PDGFRA switch-control tyrosine kinase inhibitor studied
    in KIT-altered metastatic melanoma. Phase I expansion data showed a 23%
    confirmed objective response rate and median progression-free survival of
    7.3 months.
  evidence:
  - reference: PMID:35753087
    reference_title: Efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Confirmed objective response rate (ORR) was 23%"
    explanation: Phase I expansion data support ripretinib objective responses in KIT-altered metastatic melanoma.
  - reference: PMID:35753087
    reference_title: Efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median progression-free survival (mPFS) was 7.3 months (95% CI 1.9-13.6 months)."
    explanation: Phase I expansion data support a median PFS of 7.3 months with ripretinib in KIT-altered metastatic melanoma.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: ripretinib
- name: Immune Checkpoint Inhibitors
  description: >-
    Anti-PD-1 antibodies (pembrolizumab, nivolumab) are also used in KIT-mutant
    melanoma. The optimal sequencing of KIT inhibitors versus immunotherapy
    depends on mutation status and patient characteristics.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
disease_term:
  preferred_term: acral lentiginous melanoma
  term:
    id: MONDO:0003865
    label: acral lentiginous melanoma
notes: >-
  KIT-mutant melanoma represents a distinct molecular subtype found in anatomic
  sites not typically associated with UV exposure, suggesting alternative
  pathogenic mechanisms. Testing for KIT mutations should be performed in acral,
  mucosal, and chronically sun-damaged melanomas to identify patients who may
  benefit from KIT inhibitor therapy. Response to imatinib is highly dependent
  on mutation type, with activating mutations showing better responses than
  amplification alone.

classifications:
  icdo_morphology:
    classification_value: Melanoma
  harrisons_chapter:
  - classification_value: cancer
  - classification_value: solid tumor
references:
- reference: DOI:10.1002/cncr.30663
  title: 'A phase 2 trial of dasatinib in patients with locally advanced or stage IV mucosal, acral, or vulvovaginal melanoma: A trial of the ECOG‐ACRIN Cancer Research Group (E2607)'
  found_in:
  - KIT_Mutant_Melanoma-deep-research-falcon.md
  findings:
  - statement: KIT‐directed tyrosine kinase inhibitors such as imatinib have demonstrated benefits in KIT‐mutant (KIT+) mucosal, acral, vulvovaginal, and chronically sun‐damaged (CSD) melanoma.
    supporting_text: KIT‐directed tyrosine kinase inhibitors such as imatinib have demonstrated benefits in KIT‐mutant (KIT+) mucosal, acral, vulvovaginal, and chronically sun‐damaged (CSD) melanoma.
    evidence:
    - reference: DOI:10.1002/cncr.30663
      reference_title: 'A phase 2 trial of dasatinib in patients with locally advanced or stage IV mucosal, acral, or vulvovaginal melanoma: A trial of the ECOG‐ACRIN Cancer Research Group (E2607)'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: KIT‐directed tyrosine kinase inhibitors such as imatinib have demonstrated benefits in KIT‐mutant (KIT+) mucosal, acral, vulvovaginal, and chronically sun‐damaged (CSD) melanoma.
      explanation: Deep research cited this publication as relevant literature for KIT Mutant Melanoma.
- reference: DOI:10.1016/j.esmoop.2022.100520
  title: Efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma
  found_in:
  - KIT_Mutant_Melanoma-deep-research-falcon.md
  findings:
  - statement: Efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma
    supporting_text: Efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma
- reference: DOI:10.1016/j.xcrm.2024.101435
  title: 'Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial'
  found_in:
  - KIT_Mutant_Melanoma-deep-research-falcon.md
  findings:
  - statement: 'Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial'
    supporting_text: 'Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial'
- reference: DOI:10.1038/s41416-022-01942-z
  title: Clinical and genomic correlates of imatinib response in melanomas with KIT alterations
  found_in:
  - KIT_Mutant_Melanoma-deep-research-falcon.md
  findings:
  - statement: Clinical and genomic correlates of imatinib response in melanomas with KIT alterations
    supporting_text: Clinical and genomic correlates of imatinib response in melanomas with KIT alterations
- reference: DOI:10.1093/annonc/mdx079
  title: 'Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial'
  found_in:
  - KIT_Mutant_Melanoma-deep-research-falcon.md
  findings:
  - statement: 'Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial'
    supporting_text: 'Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial'
- reference: DOI:10.1158/1078-0432.ccr-14-1630
  title: Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition
  found_in:
  - KIT_Mutant_Melanoma-deep-research-falcon.md
  findings:
  - statement: Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition
    supporting_text: 'Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown.'
    evidence:
    - reference: DOI:10.1158/1078-0432.ccr-14-1630
      reference_title: Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown.'
      explanation: Deep research cited this publication as relevant literature for KIT Mutant Melanoma.
- reference: DOI:10.1200/jco.2010.33.9275
  title: Phase II, Open-Label, Single-Arm Trial of Imatinib Mesylate in Patients With Metastatic Melanoma Harboring <i>c-Kit</i> Mutation or Amplification
  found_in:
  - KIT_Mutant_Melanoma-deep-research-falcon.md
  findings:
  - statement: Melanomas harbor aberrations in the c-Kit gene.
    supporting_text: Melanomas harbor aberrations in the c-Kit gene.
    evidence:
    - reference: DOI:10.1200/jco.2010.33.9275
      reference_title: Phase II, Open-Label, Single-Arm Trial of Imatinib Mesylate in Patients With Metastatic Melanoma Harboring <i>c-Kit</i> Mutation or Amplification
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Melanomas harbor aberrations in the c-Kit gene.
      explanation: Deep research cited this publication as relevant literature for KIT Mutant Melanoma.
- reference: DOI:10.1200/jco.2012.47.7836
  title: Imatinib for Melanomas Harboring Mutationally Activated or Amplified <i>KIT</i> Arising on Mucosal, Acral, and Chronically Sun-Damaged Skin
  found_in:
  - KIT_Mutant_Melanoma-deep-research-falcon.md
  findings:
  - statement: Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities.
    supporting_text: Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities.
    evidence:
    - reference: DOI:10.1200/jco.2012.47.7836
      reference_title: Imatinib for Melanomas Harboring Mutationally Activated or Amplified <i>KIT</i> Arising on Mucosal, Acral, and Chronically Sun-Damaged Skin
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities.
      explanation: Deep research cited this publication as relevant literature for KIT Mutant Melanoma.
- reference: DOI:10.2147/ott.s404648
  title: 'c-Kit Receptors as a Therapeutic Target in Cancer: Current Insights'
  found_in:
  - KIT_Mutant_Melanoma-deep-research-falcon.md
  findings:
  - statement: 'c-Kit Receptors as a Therapeutic Target in Cancer: Current Insights'
    supporting_text: 'c-Kit Receptors as a Therapeutic Target in Cancer: Current Insights'
- reference: DOI:10.3390/genes14051021
  title: The Genomic Landscape of Melanoma and Its Therapeutic Implications
  found_in:
  - KIT_Mutant_Melanoma-deep-research-falcon.md
  findings:
  - statement: Melanoma is one of the most aggressive malignancies of the skin.
    supporting_text: Melanoma is one of the most aggressive malignancies of the skin.
    evidence:
    - reference: DOI:10.3390/genes14051021
      reference_title: The Genomic Landscape of Melanoma and Its Therapeutic Implications
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Melanoma is one of the most aggressive malignancies of the skin.
      explanation: Deep research cited this publication as relevant literature for KIT Mutant Melanoma.
- reference: DOI:10.3390/ijms252010885
  title: 'Detection of KIT Mutations in Systemic Mastocytosis: How, When, and Why'
  found_in:
  - KIT_Mutant_Melanoma-deep-research-falcon.md
  findings:
  - statement: 'Detection of KIT Mutations in Systemic Mastocytosis: How, When, and Why'
    supporting_text: More than 90% of patients affected by mastocytosis are characterized by a somatic point mutation of KIT, which induces ligand-independent activation of the receptor and downstream signal triggering, ultimately leading to mast cell accumulation and survival.
    evidence:
    - reference: DOI:10.3390/ijms252010885
      reference_title: 'Detection of KIT Mutations in Systemic Mastocytosis: How, When, and Why'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: More than 90% of patients affected by mastocytosis are characterized by a somatic point mutation of KIT, which induces ligand-independent activation of the receptor and downstream signal triggering, ultimately leading to mast cell accumulation and survival.
      explanation: Deep research cited this publication as relevant literature for KIT Mutant Melanoma.

📚

References & Deep Research

References

DOI:10.1002/cncr.30663

A phase 2 trial of dasatinib in patients with locally advanced or stage IV mucosal, acral, or vulvovaginal melanoma: A trial of the ECOG‐ACRIN Cancer Research Group (E2607)

1 finding

KIT‐directed tyrosine kinase inhibitors such as imatinib have demonstrated benefits in KIT‐mutant (KIT+) mucosal, acral, vulvovaginal, and chronically sun‐damaged (CSD) melanoma.

"KIT‐directed tyrosine kinase inhibitors such as imatinib have demonstrated benefits in KIT‐mutant (KIT+) mucosal, acral, vulvovaginal, and chronically sun‐damaged (CSD) melanoma."

Show evidence (1 reference)

DOI:10.1002/cncr.30663 SUPPORT Human Clinical

"KIT‐directed tyrosine kinase inhibitors such as imatinib have demonstrated benefits in KIT‐mutant (KIT+) mucosal, acral, vulvovaginal, and chronically sun‐damaged (CSD) melanoma."

Deep research cited this publication as relevant literature for KIT Mutant Melanoma.

DOI:10.1016/j.esmoop.2022.100520

Efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma

1 finding

Efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma

"Efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma"

DOI:10.1016/j.xcrm.2024.101435

Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial

1 finding

Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial

"Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial"

DOI:10.1038/s41416-022-01942-z

Clinical and genomic correlates of imatinib response in melanomas with KIT alterations

1 finding

Clinical and genomic correlates of imatinib response in melanomas with KIT alterations

"Clinical and genomic correlates of imatinib response in melanomas with KIT alterations"

DOI:10.1093/annonc/mdx079

Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial

1 finding

Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial

"Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial"

DOI:10.1158/1078-0432.ccr-14-1630

Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition

1 finding

Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition

"Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown."

Show evidence (1 reference)

DOI:10.1158/1078-0432.ccr-14-1630 SUPPORT Human Clinical

Deep research cited this publication as relevant literature for KIT Mutant Melanoma.

DOI:10.1200/jco.2010.33.9275

Phase II, Open-Label, Single-Arm Trial of Imatinib Mesylate in Patients With Metastatic Melanoma Harboring <i>c-Kit</i> Mutation or Amplification

1 finding

Melanomas harbor aberrations in the c-Kit gene.

"Melanomas harbor aberrations in the c-Kit gene."

Show evidence (1 reference)

DOI:10.1200/jco.2010.33.9275 SUPPORT Human Clinical

"Melanomas harbor aberrations in the c-Kit gene."

Deep research cited this publication as relevant literature for KIT Mutant Melanoma.

DOI:10.1200/jco.2012.47.7836

Imatinib for Melanomas Harboring Mutationally Activated or Amplified <i>KIT</i> Arising on Mucosal, Acral, and Chronically Sun-Damaged Skin

1 finding

Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities.

"Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities."

Show evidence (1 reference)

DOI:10.1200/jco.2012.47.7836 SUPPORT Human Clinical

"Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities."

Deep research cited this publication as relevant literature for KIT Mutant Melanoma.

DOI:10.2147/ott.s404648

c-Kit Receptors as a Therapeutic Target in Cancer: Current Insights

1 finding

c-Kit Receptors as a Therapeutic Target in Cancer: Current Insights

"c-Kit Receptors as a Therapeutic Target in Cancer: Current Insights"

DOI:10.3390/genes14051021

The Genomic Landscape of Melanoma and Its Therapeutic Implications

1 finding

Melanoma is one of the most aggressive malignancies of the skin.

"Melanoma is one of the most aggressive malignancies of the skin."

Show evidence (1 reference)

DOI:10.3390/genes14051021 SUPPORT Human Clinical

"Melanoma is one of the most aggressive malignancies of the skin."

Deep research cited this publication as relevant literature for KIT Mutant Melanoma.

DOI:10.3390/ijms252010885

Detection of KIT Mutations in Systemic Mastocytosis: How, When, and Why

1 finding

Detection of KIT Mutations in Systemic Mastocytosis: How, When, and Why

"More than 90% of patients affected by mastocytosis are characterized by a somatic point mutation of KIT, which induces ligand-independent activation of the receptor and downstream signal triggering, ultimately leading to mast cell accumulation and survival."

Show evidence (1 reference)

DOI:10.3390/ijms252010885 SUPPORT Human Clinical

Deep research cited this publication as relevant literature for KIT Mutant Melanoma.

Deep Research

Falcon ▸

1. Disease Information

Edison Scientific Literature 37 citations 2026-04-05T17:54:20.903865

1. Disease Information

Overview / definition

KIT-mutant melanoma refers to melanoma in which KIT (CD117) proto-oncogene receptor tyrosine kinase is altered in a way that functionally drives tumor behavior (typically activating point mutations/indels, sometimes with concurrent copy-number gain). Clinically, KIT-driven melanomas are most often described in mucosal, acral, and chronically sun-damaged primary sites, and are therapeutically relevant because they can be sensitive to KIT tyrosine kinase inhibitors (TKIs) when activating KIT mutations are present. In a key phase II trial, the investigators framed the actionable setting as “metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations,” and concluded that such melanomas “should be assessed for KIT mutations” because imatinib “can be effective when tumors harbor KIT mutations, but not if KIT is amplified only.” (hodi2013imatinibformelanomas pages 1-2)

Common synonyms / alternative names

KIT-altered melanoma
KIT-driven melanoma
c-KIT-mutated melanoma / CD117-mutant melanoma
KIT-mutant acral melanoma; KIT-mutant mucosal melanoma

Aggregation level of evidence

The characterization here is derived primarily from aggregated disease-level resources (genomic subtype reviews) and prospective clinical trials enrolling defined KIT-altered populations, rather than individual EHR-derived case series (yang2023thegenomiclandscape pages 2-4, larkin2024nilotinibinkitdriven pages 3-5, guo2011phaseiiopenlabel pages 1-2, hodi2013imatinibformelanomas pages 1-2, guo2017efficacyandsafety pages 1-7).

2. Etiology

Disease causal factors

Primary causal factor (molecular): somatic activating alterations in KIT, a receptor tyrosine kinase, producing constitutive or exaggerated pro-survival/proliferation signaling through canonical RTK pathways (PI3K/AKT, MAPK/ERK, JAK/STAT, SRC family pathways) (cilloni2024detectionofkit pages 3-5, abdellateif2023ckitreceptorsas pages 1-2).

Risk factors

Evidence in the retrieved corpus supports subtype and anatomic-site association rather than classic exposure-based risk factors: - KIT alterations are uncommon overall but enriched in mucosal and acral melanomas, and occur in a subset of melanomas on chronically sun-damaged skin (jung2022clinicalandgenomic pages 1-2).

Protective factors / gene–environment interactions

Not identified in the retrieved sources.

3. Phenotypes (clinical presentation)

Because KIT-mutant melanoma is a molecular subtype spanning multiple anatomic melanoma subtypes, phenotype is best summarized by the parent clinicopathologic subtype.

Acral melanoma phenotypes

Acral melanoma arises from palmar/plantar/nail unit melanocytes and has distinct biology and typically worse outcomes than non-acral cutaneous melanoma (yang2023thegenomiclandscape pages 2-4). Suggested phenotypes and ontology mappings: - Acral primary site involvement (UBERON: e.g., skin of palm, skin of sole, nail unit). - Advanced-stage presentation / metastatic disease at diagnosis (HPO: Neoplasm metastasis [HP:0003002]).

Mucosal melanoma phenotypes

Mucosal melanoma arises from mucosal melanocytes (anatomic sites vary: sinonasal, anorectal, vulvovaginal, etc.). In molecular surveys, KIT is commonly the most frequent driver in mucosal melanoma (yang2023thegenomiclandscape pages 2-4). Suggested mappings: - Mucosal primary site involvement (UBERON: mucosa plus site-specific terms). - Local invasion and metastasis (HPO: HP:0003002).

HPO term suggestions (general melanoma manifestations)

Neoplasm of the skin / melanoma: Cutaneous melanoma (disease concept; HPO terms may vary by knowledge base)
Metastatic disease: HP:0003002 (Neoplasm metastasis)
Lymph node metastasis: HP:0001416 (if present clinically)

Frequency/severity/progression: Specific symptom-level frequencies (pain, bleeding, etc.) are not quantified in the retrieved sources; the strongest quantitative phenotype-like data available are subtype distributions and treatment responses by subtype and genotype (jung2022clinicalandgenomic pages 4-5, larkin2024nilotinibinkitdriven pages 5-6).

4. Genetic / Molecular Information

Causal gene

KIT (KIT proto-oncogene, receptor tyrosine kinase)

Pathogenic variant spectrum (melanoma)

KIT alterations in melanoma are heterogeneous and can involve multiple exons. Across imatinib- and nilotinib-era data, responses are enriched in exon 11 and exon 13 alterations, particularly L576P (exon 11) and K642E (exon 13) (jung2022clinicalandgenomic pages 1-2, guo2011phaseiiopenlabel pages 1-2).

Subtype enrichment and mutation frequency: - In a 2023 genomic review summarizing multiple studies, KIT mutation frequency was 1.8% in “UV-related” melanomas, 10.9–24.4% in acral melanoma, and 19.1–23.1% in mucosal melanoma (yang2023thegenomiclandscape pages 4-5, yang2023thegenomiclandscape media 3d8ffda1). - Another 2022 pooled analysis summarizes that KIT alterations are ~1–7% overall, enriched to ~10–20% in mucosal and acral melanoma, and ~1–2% in melanomas arising from chronically sun-damaged skin (jung2022clinicalandgenomic pages 1-2).

Somatic vs germline

The clinical trials and genomic reviews accessed describe KIT alterations as tumor (somatic) alterations in advanced melanoma populations (guo2011phaseiiopenlabel pages 1-2, hodi2013imatinibformelanomas pages 1-2, guo2017efficacyandsafety pages 1-7, janku2022efficacyandsafety pages 3-4). Germline predisposition was not addressed in the retrieved sources.

Functional consequences / mechanism (molecular chain)

Upstream trigger: activating KIT mutation (e.g., juxtamembrane/kinase-domain variants) → ligand-independent or dysregulated RTK signaling.
Receptor activation and phosphorylation: SCF binding normally induces KIT dimerization and autophosphorylation; in cancer, gain-of-function KIT alterations can cause constitutive activation (cilloni2024detectionofkit pages 3-5, abdellateif2023ckitreceptorsas pages 1-2).
Downstream signaling: activation of PI3K/AKT (survival/proliferation), MAPK/ERK (transcription/proliferation), SRC kinases (motility/angiogenesis), and JAK/STAT (transcription programs) (cilloni2024detectionofkit pages 3-5, abdellateif2023ckitreceptorsas pages 1-2).
Cellular outcomes: sustained proliferation and apoptosis resistance → tumor growth and metastasis potential.

Suggested GO (biological process) terms

GO:0007169 transmembrane receptor protein tyrosine kinase signaling pathway
GO:0008284 positive regulation of cell population proliferation
GO:0043065 positive regulation of apoptotic process (context-specific; KIT signaling can inhibit apoptosis)
GO:0000165 MAPK cascade
GO:0014066 regulation of phosphatidylinositol 3-kinase signaling

Suggested Cell Ontology (CL) terms

CL:0000148 melanocyte (primary lineage cell)
CL:0000236 B cell / CL:0000624 CD8-positive, alpha-beta T cell (relevant to tumor microenvironment discussions, especially when considering immunotherapy combinations; mechanistic immunology was not deeply quantified in retrieved sources)

5. Environmental Information

No KIT-mutant-specific environmental triggers were identified in the retrieved sources. KIT-mutant melanoma is instead primarily associated with anatomic subtype and non-UV (acral/mucosal) biology (yang2023thegenomiclandscape pages 2-4, jung2022clinicalandgenomic pages 1-2).

6. Mechanism / Pathophysiology

Key pathways

PI3K/AKT and MAPK/ERK are emphasized as principal downstream effector pathways of c-KIT signaling, promoting survival and proliferation, while SRC and JAK/STAT contribute to motility/angiogenesis and transcriptional programs (cilloni2024detectionofkit pages 3-5, abdellateif2023ckitreceptorsas pages 1-2).

Resistance mechanisms (clinical inference)

In the imatinib phase II trial across mucosal/acral/CSD melanoma, “NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.” (hodi2013imatinibformelanomas pages 1-2)
In the ripretinib phase I expansion, prior KIT inhibitor exposure was associated with lower ORR and shorter median PFS compared with KIT-inhibitor–naïve patients (janku2022efficacyandsafety pages 1-2, janku2022efficacyandsafety pages 4-5).

7. Anatomical Structures Affected

Primary sites (by subtype)

Acral skin structures: palm/sole/nail unit (UBERON mappings as above) (yang2023thegenomiclandscape pages 2-4)
Mucosal surfaces (site-specific mucosa) (yang2023thegenomiclandscape pages 2-4)
Chronically sun-damaged skin (head/neck or other chronically UV-exposed skin; CSD category used for trial eligibility) (hodi2013imatinibformelanomas pages 1-2)

Metastatic sites

Common metastatic patterns are not enumerated in retrieved sources; advanced/metastatic disease is the predominant study population across trials (guo2011phaseiiopenlabel pages 1-2, hodi2013imatinibformelanomas pages 1-2, guo2017efficacyandsafety pages 1-7, janku2022efficacyandsafety pages 3-4).

8. Temporal Development

Onset

Typically adult-onset melanoma; age distribution not comprehensively extracted in the present evidence set.

Progression

KIT-mutant melanomas in trials are often advanced/metastatic. In multiple TKI trials, median PFS is generally on the order of months (see Treatment section), consistent with the common clinical observation that responses—when present—may be clinically meaningful but not uniformly durable (guo2011phaseiiopenlabel pages 1-2, hodi2013imatinibformelanomas pages 5-6, guo2017efficacyandsafety pages 1-7).

9. Inheritance and Population

Epidemiology (mutation frequency by subtype)

A 2023 genomic synthesis reported KIT mutation frequencies by subtype (compiled from multiple cohorts): - UV-related melanoma: 1.8% - Acral melanoma: 10.9–24.4% - Mucosal melanoma: 19.1–23.1% (Visual evidence: Table 2 in the review) (yang2023thegenomiclandscape pages 4-5, yang2023thegenomiclandscape media 3d8ffda1)

Another pooled clinical genomics analysis summarizes KIT alterations at: - ~1–7% overall melanoma - ~10–20% in mucosal melanoma - ~10–20% in acral melanoma - ~1–2% in chronically sun-damaged skin melanomas (jung2022clinicalandgenomic pages 1-2)

Population demographics

Not robustly extractable from the retrieved sources beyond subtype enrichment.

10. Diagnostics

Molecular testing approach (tumor)

Key trials used targeted KIT exon sequencing to identify actionable mutations. - NICAM eligibility required tumors with KIT mutations screened by “Sanger sequencing of exons 9, 11, 13 and 17” (larkin2024nilotinibinkitdriven pages 14-15). - Hodi et al. enrolled patients with KIT “amplifications and/or mutations” but the strongest benefit was in mutation-positive disease (hodi2013imatinibformelanomas pages 1-2).

KIT amplification assessment

In NICAM, KIT amplification was assessed exploratorily by FISH on archival FFPE (larkin2024nilotinibinkitdriven pages 14-15).
In Hodi et al., objective responses were absent in amplification-only tumors, supporting mutation-first prioritization for predicting TKI response (hodi2013imatinibformelanomas pages 1-2).

Liquid biopsy / ctDNA (recent implementation)

NICAM provides notable contemporary evidence for ctDNA-based KIT testing: - “concordance between ctDNA and matched FFPE tumor mutation calls was 100%” (larkin2024nilotinibinkitdriven pages 6-8). - Authors state that “ddPCR-based KIT analysis appears feasible and accu-rate for KIT testing in patients with metastatic MM and AM and could be proposed for liquid biopsies testing” (larkin2024nilotinibinkitdriven pages 9-10).

Differential diagnosis

Not detailed in retrieved sources; in practice, differential diagnosis is dominated by distinguishing melanoma subtype and excluding alternative primary sites and other oncogene drivers (BRAF/NRAS/NF1), but detailed diagnostic criteria and pathology differentials were not accessed here.

11. Outcome / Prognosis

Prognostic notes (treatment-linked)

Prognosis in KIT-mutant melanoma is heterogeneous and strongly influenced by stage and treatment responsiveness. Across KIT TKI trials, median OS values ranged from ~7–18 months depending on study era, population, and treatment line (e.g., NICAM 7.7 months; TEAM 18.0 months; Hodi imatinib 12.5 months) (larkin2024nilotinibinkitdriven pages 5-6, hodi2013imatinibformelanomas pages 5-6, guo2017efficacyandsafety pages 1-7).

12. Treatment

Current applications (real-world implementation)

The principal real-world application is genotype-guided use of KIT TKIs in advanced KIT-mutant melanoma (especially acral/mucosal/CSD primary sites). A central practical point supported by a prospective trial is that KIT amplification without activating mutation is not a reliable predictor of imatinib response (hodi2013imatinibformelanomas pages 1-2).

Key clinical evidence (prospective trials)

Study (year, journal)	Population/subtype and KIT alteration eligibility	N	Key outcomes (ORR/BORR, DCR, median PFS/TTP, median OS)	Key genotype associations (exon/variant)	Notes
Imatinib — Guo 2011, J Clin Oncol	Metastatic melanoma with c-KIT mutation or amplification; open-label single-arm phase II (guo2011phaseiiopenlabel pages 1-2)	43	ORR 23.3% (10/43); DCR 53.5% (10 PR + 13 SD); median PFS 3.5 mo; 6-mo PFS 36.6%; 1-y OS 51.0% (guo2011phaseiiopenlabel pages 1-2)	9/10 PRs occurred in exon 11 or 13 mutations (guo2011phaseiiopenlabel pages 1-2)	Dose escalation to 800 mg/d rarely restored disease control (guo2011phaseiiopenlabel pages 1-2)
Imatinib — Hodi 2013, J Clin Oncol	Metastatic mucosal, acral, or chronically sun-damaged melanoma with KIT amplification and/or mutation; multicenter phase II (hodi2013imatinibformelanomas pages 1-2)	25 enrolled; 24 evaluable	BORR 29% (21% excluding nonconfirmed responses); DCR 50%; overall TTP 3.7 mo; OS 12.5 mo (hodi2013imatinibformelanomas pages 1-2, hodi2013imatinibformelanomas pages 5-6)	KIT-mutated tumors: BORR 7/13 (54%), DCR 77%; KIT amplified-only tumors: BORR 0%, DCR 18% (hodi2013imatinibformelanomas pages 1-2, hodi2013imatinibformelanomas pages 3-4)	Amplification-only lacked objective responses; pretreatment NRAS mutations and KIT copy-number gain implicated in resistance (hodi2013imatinibformelanomas pages 1-2, hodi2013imatinibformelanomas pages 5-6)
Nilotinib — Carvajal 2015, Clin Cancer Res	Melanoma with KIT mutations or amplification after prior KIT inhibitor; cohort A refractory/intolerant to prior KIT inhibitor, cohort B brain metastases (carvajal2015phaseiistudy pages 1-3)	20 enrolled; 19 treated	Cohort A primary endpoint achieved in 27%; cohort B 12.5%; ORR 18.2% in cohort A, 0 in cohort B; median TTP 3.3 mo; median OS 9.1 mo (carvajal2015phaseiistudy pages 1-3)	Maintains activity against a range of exon 9, 11, and 13 KIT mutations (carvajal2015phaseiistudy pages 1-3)	Limited efficacy in brain metastases (carvajal2015phaseiistudy pages 1-3)
Nilotinib — TEAM 2017, Ann Oncol	Advanced/inoperable KIT-mutated melanoma without prior KIT inhibitor; global single-arm phase II (guo2017efficacyandsafety pages 1-7)	42	ORR 26.2% (11/42); all responses PRs; median response duration 7.1 mo; median PFS 4.2 mo; 6-mo PFS 34.6%; median OS 18.0 mo (guo2017efficacyandsafety pages 7-12, guo2017efficacyandsafety pages 1-7)	10/11 responders had exon 11 mutations; exon 11 PR rate 10/26 (38.5%), exon 13 PR rate 1/13 (7.7%), exon 9/17 no responses; 4 responders had L576P (guo2017efficacyandsafety pages 7-12, guo2017efficacyandsafety pages 1-7)	Activity similar to historical imatinib, strongest in exon 11/L576P (guo2017efficacyandsafety pages 1-7)
Nilotinib — NICAM 2024, Cell Reports Medicine	KIT-mutated metastatic mucosal and acral melanoma; single-arm phase II; prior TKI excluded; exploratory KIT amplification/FISH and ctDNA ddPCR analyses (larkin2024nilotinibinkitdriven pages 14-15, larkin2024nilotinibinkitdriven pages 1-3)	29 treated; 26 evaluable	6-mo PFS by local review 25%; by central review 29%; OR at 12 wk 19% (5/26); median PFS 3.7 mo; median OS 7.7 mo; 12-mo OS 44% (larkin2024nilotinibinkitdriven pages 3-5, larkin2024nilotinibinkitdriven pages 5-6)	Mutations concentrated in exon 11 (69%), exon 13 (14%), exon 17 (14%), exon 9 (3%); OR at 12 wk: exon 11 16%, exon 13 25%, exon 17 67%; median PFS: exon 11 2.9 mo, exon 13 2.3 mo, exon 17 5.4 mo; L576 in 31% (larkin2024nilotinibinkitdriven pages 3-5, larkin2024nilotinibinkitdriven pages 5-6, larkin2024nilotinibinkitdriven pages 8-9)	Acral tumors had worse median PFS/OS than mucosal; ctDNA/FFPE concordance 100%; KIT copy number not clearly associated with outcome (larkin2024nilotinibinkitdriven pages 5-6, larkin2024nilotinibinkitdriven pages 6-8, larkin2024nilotinibinkitdriven pages 8-9)
Dasatinib — E2607 2017, Cancer	Locally advanced or stage IV mucosal, acral, vulvovaginal melanoma; stage I included KIT-mutant and KIT−; stage II restricted to KIT+ (kalinsky2017aphase2 pages 1-2)	51 analyzable stage I; 22 analyzable stage II; 73 evaluable overall	Stage I PR 3/51 (5.9%); stage II PR 4/22 (18.2%); median response duration 4.2 mo; median PFS 2.1 mo; median OS 7.5 mo (kalinsky2017aphase2 pages 1-2, kalinsky2017aphase2 pages 4-5)	Among exon 11 and/or 13 KIT mutations, PR rate 20%; median PFS 4.7 mo; no responses with common L576P and K642E in one analysis, but responses seen with P577-D579 deletion and dual exon 11/13 mutations (kalinsky2017aphase2 pages 4-5, kalinsky2017aphase2 pages 7-8)	Exploratory analyses found no significant PFS/OS difference by overall KIT status; authors concluded response rate lower than expected and imatinib should remain KIT TKI of choice (kalinsky2017aphase2 pages 7-8, kalinsky2017aphase2 pages 1-2)
Ripretinib — Janku 2022, ESMO Open	KIT-altered metastatic melanoma phase I expansion; KIT mutation and/or amplification; heavily pretreated; starting dose 150 mg QD, BID escalation after progression allowed (janku2022efficacyandsafety pages 1-2, janku2022efficacyandsafety pages 2-3)	26	Confirmed ORR 23% (95% CI 9–44); among patients with follow-up imaging ORR 32% (8/25; CR 1, PR 7); median duration of confirmed response 9.1 mo; median PFS 7.3 mo (janku2022efficacyandsafety pages 5-6, janku2022efficacyandsafety pages 1-2, janku2022efficacyandsafety pages 3-4)	Confirmed ORR 44% in exon 11 and 18% in exon 17; median PFS 10.2 mo (exon 11) and 13.6 mo (exon 17); examples of responses include exon 11 L576P, exon 17 D820Y, exon 17 Y823D; D816V associated with PD in one case (janku2022efficacyandsafety pages 5-6, janku2022efficacyandsafety pages 4-5, janku2022efficacyandsafety pages 3-4)	KIT-inhibitor–naive patients had ORR 29% and mPFS 10.2 mo vs prior KIT inhibitor ORR 11% and mPFS 2.9 mo (janku2022efficacyandsafety pages 1-2, janku2022efficacyandsafety pages 4-5)

Table: This table summarizes key prospective clinical evidence for KIT-altered melanoma therapies across major studies of imatinib, nilotinib, dasatinib, and ripretinib. It highlights outcomes, genotype-response patterns, and practical caveats such as amplification-only disease and prior KIT inhibitor exposure.

Imatinib (KIT TKI)

Guo et al., JCO 2011 (published Jul 2011): ORR 23.3%, DCR 53.5%, median PFS 3.5 months; 9/10 PRs in exon 11 or 13 (guo2011phaseiiopenlabel pages 1-2).
Hodi et al., JCO 2013 (published Sep 2013): BORR 29% overall; BORR 54% in KIT-mutated vs 0% in amplification-only tumors; median TTP 3.7 months; median OS 12.5 months (hodi2013imatinibformelanomas pages 1-2, hodi2013imatinibformelanomas pages 5-6).

Nilotinib (KIT TKI)

TEAM trial, Annals of Oncology 2017 (published Mar 2017): ORR 26.2%, median response duration 7.1 months, median PFS 4.2 months, median OS 18.0 months; responses concentrated in exon 11 (guo2017efficacyandsafety pages 1-7, guo2017efficacyandsafety pages 7-12).
NICAM, Cell Reports Medicine 2024 (published Feb 2024): OR at 12 weeks 19% (5/26), median PFS 3.7 months, median OS 7.7 months; mutations concentrated in exon 11 (69%); ctDNA ddPCR feasibility and 100% ctDNA–FFPE concordance reported (larkin2024nilotinibinkitdriven pages 3-5, larkin2024nilotinibinkitdriven pages 5-6, larkin2024nilotinibinkitdriven pages 6-8).
Carvajal et al., Clin Cancer Res 2015 (published May 2015): post-imatinib setting; ORR 18.2% in the prior KIT-inhibitor cohort; limited activity in brain metastases cohort; median TTP 3.3 months; median OS 9.1 months (carvajal2015phaseiistudy pages 1-3).

Dasatinib (multi-kinase/SRC and KIT activity)

E2607 (Cancer 2017, published Jul 2017): modest activity; median PFS 2.1 months, median OS 7.5 months; authors conclude low response rate and recommend imatinib remain KIT TKI of choice in unresectable KIT+ melanoma (kalinsky2017aphase2 pages 1-2).

Ripretinib (switch-control TKI; KIT/PDGFRA)

Janku et al., ESMO Open 2022 (published Aug 2022): confirmed ORR 23% (95% CI 9–44) with median PFS 7.3 months and median response duration 9.1 months; activity differed by exon and prior KIT inhibitor exposure (KIT-inhibitor–naïve ORR 29% and mPFS 10.2 months vs prior KIT inhibitor ORR 11% and mPFS 2.9 months) (janku2022efficacyandsafety pages 1-2, janku2022efficacyandsafety pages 4-5).

MAXO term suggestions (treatments/actions)

Tyrosine kinase inhibitor therapy (MAXO: TKI treatment)
Molecular targeted therapy (MAXO: targeted therapy)
Tumor mutation profiling / genomic sequencing (MAXO: genetic test / tumor genomic profiling)
Liquid biopsy (MAXO: liquid biopsy testing)

13. Prevention

No KIT-mutant-specific prevention strategies were identified in the retrieved sources. General melanoma prevention and early detection principles apply, but are not addressed in the accessed KIT-focused literature.

14. Other Species / Natural Disease

Not supported by the retrieved evidence set.

15. Model Organisms

The retrieved evidence set does not provide detailed descriptions of KIT-mutant melanoma animal models or engineered systems. (This is a gap for the current report.)

Recent Developments (2023–2024 emphasis)

2024 NICAM trial (nilotinib; metastatic mucosal/acral KIT-mutant melanoma) provides updated prospective efficacy estimates (median PFS 3.7 months; OR at 12 weeks 19%) and highlights a clinically actionable diagnostic development: plasma ddPCR ctDNA testing with 100% concordance to tumor calls in available matched samples (larkin2024nilotinibinkitdriven pages 3-5, larkin2024nilotinibinkitdriven pages 5-6, larkin2024nilotinibinkitdriven pages 6-8).
2023 genomic synthesis consolidates KIT mutation frequency ranges across melanoma subtypes, providing a practical expectation for testing yield by subtype (yang2023thegenomiclandscape pages 4-5, yang2023thegenomiclandscape media 3d8ffda1).

Visual evidence (mutation frequency by subtype)

The figure below (Table 2 from a 2023 review) provides the subtype-specific KIT mutation frequencies used in the epidemiology section (yang2023thegenomiclandscape media 3d8ffda1).

Key Statistics (quick reference)

KIT mutation frequency: UV-related ~1.8%, acral 10.9–24.4%, mucosal 19.1–23.1% (yang2023thegenomiclandscape pages 4-5, yang2023thegenomiclandscape media 3d8ffda1).
Imatinib (KIT-mutated vs amplification-only): BORR 54% vs 0% in a phase II trial enrolling mucosal/acral/CSD melanoma with KIT alterations (hodi2013imatinibformelanomas pages 1-2).
Nilotinib (TEAM trial): ORR 26.2%, median PFS 4.2 months, median OS 18.0 months (guo2017efficacyandsafety pages 1-7).
Ripretinib phase I expansion: confirmed ORR 23%, median PFS 7.3 months; KIT-inhibitor–naïve subgroup had higher ORR and longer PFS (janku2022efficacyandsafety pages 1-2).

Limitations of this report

Formal ontology identifiers (MONDO/MeSH/ICD-10/11) and comprehensive phenotype/quality-of-life metrics were not available in the retrieved corpus and would require dedicated searches in OMIM/Orphanet/MeSH/MONDO resources.
Model-organism and non-human disease information for KIT-mutant melanoma was not captured in the currently retrieved sources.

References

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(guo2017efficacyandsafety pages 7-12): Jun Guo, Richard D. Carvajal, Reinhard Dummer, A. Hauschild, A. Daud, Boris C. Bastian, S. Markovic, P. Queirolo, A. Arance, Carola Berking, V. Camargo, D. Herchenhorn, T. M. Petrella, D. Schadendorf, W. Sharfman, Alessandro Testori, S. Novick, S. Hertle, C. Nourry, Q. Chen, and F. Hodi. Efficacy and safety of nilotinib in patients with kit-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase ii team trial. Annals of Oncology, 28:1380-1387, Mar 2017. URL: https://doi.org/10.1093/annonc/mdx079, doi:10.1093/annonc/mdx079. This article has 212 citations and is from a highest quality peer-reviewed journal.
(larkin2024nilotinibinkitdriven pages 1-3): James Larkin, Richard Marais, Nuria Porta, David Gonzalez de Castro, Lisa Parsons, Christina Messiou, Gordon Stamp, Lisa Thompson, Kim Edmonds, Sarah Sarker, Jane Banerji, Paul Lorigan, Thomas R Jeffry Evans, Pippa Corrie, Ernest Marshall, Mark R Middleton, Paul Nathan, Steve Nicholson, Christian Ottensmeier, Ruth Plummer, Judith Bliss, Sara Valpione, and Samra Turajlic. Nilotinib in kit-driven advanced melanoma: results from the phase ii single-arm nicam trial. Cell Reports Medicine, Feb 2024. URL: https://doi.org/10.1016/j.xcrm.2024.101435, doi:10.1016/j.xcrm.2024.101435. This article has 21 citations and is from a peer-reviewed journal.
(larkin2024nilotinibinkitdriven pages 8-9): James Larkin, Richard Marais, Nuria Porta, David Gonzalez de Castro, Lisa Parsons, Christina Messiou, Gordon Stamp, Lisa Thompson, Kim Edmonds, Sarah Sarker, Jane Banerji, Paul Lorigan, Thomas R Jeffry Evans, Pippa Corrie, Ernest Marshall, Mark R Middleton, Paul Nathan, Steve Nicholson, Christian Ottensmeier, Ruth Plummer, Judith Bliss, Sara Valpione, and Samra Turajlic. Nilotinib in kit-driven advanced melanoma: results from the phase ii single-arm nicam trial. Cell Reports Medicine, Feb 2024. URL: https://doi.org/10.1016/j.xcrm.2024.101435, doi:10.1016/j.xcrm.2024.101435. This article has 21 citations and is from a peer-reviewed journal.
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(kalinsky2017aphase2 pages 4-5): Kevin Kalinsky, Sandra Lee, Krista M. Rubin, Donald P. Lawrence, Anthony J. Iafrarte, Darell R. Borger, Kim A. Margolin, Mario M. Leitao, Ahmad A. Tarhini, Henry B. Koon, Andrew L. Pecora, Anthony J. Jaslowski, Gary I. Cohen, Timothy M. Kuzel, Christopher D. Lao, and John M. Kirkwood. A phase 2 trial of dasatinib in patients with locally advanced or stage iv mucosal, acral, or vulvovaginal melanoma: a trial of the ecog‐acrin cancer research group (e2607). Cancer, 123:2688-2697, Jul 2017. URL: https://doi.org/10.1002/cncr.30663, doi:10.1002/cncr.30663. This article has 137 citations and is from a domain leading peer-reviewed journal.
(kalinsky2017aphase2 pages 7-8): Kevin Kalinsky, Sandra Lee, Krista M. Rubin, Donald P. Lawrence, Anthony J. Iafrarte, Darell R. Borger, Kim A. Margolin, Mario M. Leitao, Ahmad A. Tarhini, Henry B. Koon, Andrew L. Pecora, Anthony J. Jaslowski, Gary I. Cohen, Timothy M. Kuzel, Christopher D. Lao, and John M. Kirkwood. A phase 2 trial of dasatinib in patients with locally advanced or stage iv mucosal, acral, or vulvovaginal melanoma: a trial of the ecog‐acrin cancer research group (e2607). Cancer, 123:2688-2697, Jul 2017. URL: https://doi.org/10.1002/cncr.30663, doi:10.1002/cncr.30663. This article has 137 citations and is from a domain leading peer-reviewed journal.
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OpenScientist Report

Classifications

Subtypes

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Treatments

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

Overview / definition

Common synonyms / alternative names

Aggregation level of evidence

2. Etiology

Disease causal factors

Risk factors

Protective factors / gene–environment interactions

3. Phenotypes (clinical presentation)

Acral melanoma phenotypes

Mucosal melanoma phenotypes

HPO term suggestions (general melanoma manifestations)

4. Genetic / Molecular Information

Causal gene

Pathogenic variant spectrum (melanoma)

Somatic vs germline

Functional consequences / mechanism (molecular chain)

Suggested GO (biological process) terms

Suggested Cell Ontology (CL) terms

5. Environmental Information

6. Mechanism / Pathophysiology

Key pathways

Resistance mechanisms (clinical inference)

7. Anatomical Structures Affected

Primary sites (by subtype)

Metastatic sites

8. Temporal Development

Onset

Progression

9. Inheritance and Population

Epidemiology (mutation frequency by subtype)

Population demographics

10. Diagnostics

Molecular testing approach (tumor)

KIT amplification assessment

Liquid biopsy / ctDNA (recent implementation)

Differential diagnosis

11. Outcome / Prognosis

Prognostic notes (treatment-linked)

12. Treatment

Current applications (real-world implementation)

Key clinical evidence (prospective trials)

Imatinib (KIT TKI)

Nilotinib (KIT TKI)

Dasatinib (multi-kinase/SRC and KIT activity)

Ripretinib (switch-control TKI; KIT/PDGFRA)

MAXO term suggestions (treatments/actions)

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Recent Developments (2023–2024 emphasis)

Visual evidence (mutation frequency by subtype)

Key Statistics (quick reference)

Limitations of this report