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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 13  |  Issue : 5  |  Page : 429-434

c-KIT mutation role in oral malignant melanoma pathway: A narrative review


1 Department of Health, Faculty of Vocational Studies, Universitas Airlangga, Jawa Timur, Indonesia
2 Faculty of Dental Medicine – Universitas Airlangga, Surabaya, Indonesia
3 Pakis Public Health Center, Surabaya, Indonesia

Date of Submission12-Jan-2021
Date of Decision22-Mar-2021
Date of Acceptance03-May-2021
Date of Web Publication11-Oct-2021

Correspondence Address:
Dr. Nanda Rachmad Putra Gofur
Department of Health, Faculty of Vocational Studies, Universitas Airlangga, Jawa Timur.
Indonesia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JIOH.JIOH_6_21

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  Abstract 

Aim: To investigate the role of the c-KIT mutation in oral malignant melanoma (OMM). Materials and Methods: The search strategy includes randomized control trials and clinical trials from the databases of PubMed Central, Cochrane, EBSCO, and MEDLINE from January 1999 to May 2019. A total of seven clinical trials that met all inclusion criteria were included in this systematic review. Results: A previous study found that c-KIT can initiate the activation variety of downstream pathways, including the MAPK/MEK and PI3K/AKT pathways, which play important roles in cancer development. The c-KIT mutation has resulted in a loss of heterozygosity at 12p13, and loss of p27KIP1 protein has been detected. Activating c-KIT mutations in the juxtamembrane and other domains has been considered as an oncogene and also a therapeutic target in various tumors. Conclusion: c-KIT is playing the role of an important target in the research of molecular therapy in patients with metastatic OMM with c-KIT mutations.

Keywords: c-KIT Mutation, OMM, Oral Lesion, Pathway


How to cite this article:
Gofur NR, Gofur AR, Putri HM. c-KIT mutation role in oral malignant melanoma pathway: A narrative review. J Int Oral Health 2021;13:429-34

How to cite this URL:
Gofur NR, Gofur AR, Putri HM. c-KIT mutation role in oral malignant melanoma pathway: A narrative review. J Int Oral Health [serial online] 2021 [cited 2021 Dec 3];13:429-34. Available from: https://www.jioh.org/text.asp?2021/13/5/429/327869


  Introduction Top


Melanocytes arise from neural crest cells; they are frequently found in the skin and also in mucosal membranes. Melanocytes in mucosal membranes are distributed to the oral cavity, nasal cavity, paranasal sinuses, esophagus, larynx, vagina, cervix, rectum, and anus. Melanoma results from a malignant change of melanocytes. Melanoma in the head and neck are found to comprise more than 25% of all melanomas.[1],[2],[3]

The most common sites for mucosal melanoma in order are nasal, paranasal sinuses, oral cavity, and nasopharynx. Of all mucosal melanomas, paranasal sinus has the worst prognosis. The best prognosis locations are the nasal and oral cavity. Approximately 80% of OMM develop in the mucosa of the upper jaws (maxillary anterior gingiva). The majority of these lesions occur in the keratinizing mucosa of the palate and alveolar gingivae. Lesions are frequently asymptomatic until ulceration and hemorrhage are present.[4]

Studies have found that the lip is a rare site for OMM. The incidence of melanoma in the lip might be due to the absence of melanocytes. The lip is the highest prevalent site of the melanoma palate and gingiva. Other than the palate and gingiva, the mandible, maxilla, tongue, and buccal mucosa are the most prominent sites for metastatic melanoma. A study has found that the palate is the most common site involved in OMM, with an overall prevalence of 32%–40%. The OMM incidence is 10% of melanoma of the head and neck. Among all mucosal melanomas, the sinus has the worst prognosis. The best prognosis locations are the oral cavity.[5],[6]

OMM is characterized by proliferation of malignant melanocytes along the junction between the epithelial and connective tissues as well as within the connective tissue. The most common site is the palate, which accounts for about 40% of cases followed by the buccal gingiva, which accounts for one-third of the cases. The maxillary gingiva is more commonly involved as compared with the mandibular gingiva. Other oral sites include the buccal mucosa, floor of the mouth, tongue, and lips. When encountered, melanoma of the oral cavity is more frequently found in males than in females, whereas the reverse is true in cutaneous melanomas.[7],[8]

Although OMMs are rare, they tend to be more aggressive than their cutaneous counterparts and often prove to be fatal. The prognosis for patients with oral melanoma is much worse than for those with cutaneous lesions, and the overall five-year survival rate is about 15–38%.[9],[10],[11]

The peak age for the diagnosis of mucosal melanoma is between 65 and 79 years, which is one to two decades later than for cutaneous melanoma. Mucosal melanomas are found more often in women than in men. However, in OMM, gender distribution is reported as 1:1. Melanoma of the lip has a slightly male predominance. Malignant melanoma of the mouth has a higher prevalence in blacks, Japanese, and Indians of Asia. The higher prevalence may be due to the higher published reports than actual rates.[12],[13]

Etiology is mostly unclear in malignant melanoma of the mouth. Mucosal melanoma of the mouth is not related to sun exposure. Risk factors largely remain obscure. Denture irritation, alcohol, and cigarette smoking have been listed as possible risk factors, but a direct relationship is not substantiated. Recent data indicate that c-KIT (CD117) is overexpressed in more than 80% of mucosal melanoma cases.[14],[15] This pathway is important and common in acral and mucosal melanoma, melanomas unrelated to sun exposure. KIT is a transmembrane tyrosine kinase receptor that is expressed on hematopoietic progenitor cells, melanocytes, mast cells, primordial germ cells, and interstitial cells of Cajal. Activating mutations and amplifications cause activation of growth and proliferation pathways. New drugs, such as imatinib, work on this pathway; also, this finding could use diagnostic tools in OMM. The aim of this study is to review the role of the c-KIT mutation in OMM.


  Materials and Methods Top


Search strategy

The detailed search strategies for the review were developed after identifying the included studies from different database sources. Randomized control trials and clinical trials were conducted on patients older than 17 years. PICOS framework was used in the strategy to find the journals to be reviewed:

  • A. Population / problem: the population that will analyze the problem.


  • B. Intervention: the action of intervention or enforcement in cases that occur and their explanations.


  • C. Comparison: comparison with other treatments.


  • D. Outcome: a result of research.


  • E. Study design: the research model used for review.


Keywords and data source

In searching journals, keywords (AND, OR NOT, or AND NOT) are used for more details on journal disbursement and they can simplify the search for the desired journal. Secondary data is the data used in conducting this research. The data obtained here are not directly involved in supervision, but they are obtained from previous research that has been carried out.

The data source used is the PubMed search, and it used a combination of controlled vocabulary and free text terms. The searched databases were PubMed (from January 1999 to October 2019), PubMed Advanced Search, Cochrane, EBSCO, and MEDLINE. The hand-searched journals were Operative Dentistry, Med J Islam Repub Iran, Journal of Clinical and Experimental Dentistry, and Journal of Dental Research. Inclusion and exclusion criteria are mentioned in [Table 1].
Table 1: Inclusion and exclusion criteria

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  Results Top


A study search was conducted through the database PUBMED, C using keywords: TITLE-ABS-KEY (c-KIT mutation AND oral lesion AND OMM AND pathway); 31 research articles that were obtained were included in the inclusion criteria in [Figure 1].
Figure 1: Flowchart diagram of finding topics

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The extracted data are mentioned in detail in [Table 2]. The data obtained include the name of the first author, year of publication, patient’s information (number), study design, and outcome data. The MEDLINE search used a combination of controlled vocabulary and free text terms. There were no language restrictions. The searched databases were PubMed (from January 1999 to October 2019), PubMed Advanced Search, Cochrane, EBSCO, and MEDLINE. The hand-searched journals were Operative Dentistry, Med J Islam Repub Iran, Journal of Clinical and Experimental Dentistry, and Journal of Dental Research. c-KIT mutations act as adverse prognostic factors of metastatic OMMs.
Table 2: Results table

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The c-KIT mutation was found in 10–51% of all malignant melanomas, especially OMMS. Also, all the investigators randomized the participants to interventions with a percentage, and the sequence generation was judged as being at a low risk of bias [Figure 2].
Figure 2: Risk of bias chart

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  Discussion Top


Unlike cutaneous melanomas, OMMs are largely unknown. Several hypotheses include smoking, irritation caused by dentures, and consumption of alcohol. Intraoral malignant melanomas arise from the few melanocytic cells present in the oral cavity that have the ability to undergo malignant transformation.[14],[15] They can arise de novo, from preexisting pigmented areas (5–30% cases) or from junctional nevus. In more than two-thirds of the cases, gene c-KIT mutations have been identified; they result in a loss of heterozygosity at 12p13, and a loss of p27KIP1 protein is detected. Cytogenetic analysis of melanocyte-specific gene-1 (MSG-1) marker is helpful, as it has a role in c-KIT mutation. Through this, OMM might had potential c-KIT mutations located in exons 11 and 13.[16],[17]

Genetic mutations, such as active mutations of Braf and c-Kit, may act as molecular hubs promoting the development of melanomas and, thus, can be potential therapeutic targets. Small-molecule inhibitors of both Braf (Dabrafenib) and c-Kit (Imatinib) have shown promising results for patients with advanced cutaneous melanoma.[18],[19],[20] In comparison with cutaneous melanoma, which has a high rate of Braf mutations, increasing evidence suggests that OMM harbors c-Kit mutations, indicating that imatinib, a c-Kit inhibitor, may be beneficial for patients with advanced OMM. The c-Kit gene encodes CD117, a type III transmembrane receptor tyrosine. c-Kit protein (Kit) includes five distinct domains: a glycosylated extracellular ligand binding domain (coded by exons 1–9), a hydrophobic transmembrane domain (coded by exon 10), an intracellular juxtamembrane domain (coded by exon 11), and two tyrosine kinase domains (coded by exons 12–21).[21],[22]

The intracellular juxtamembrane domain has been shown to be autoinhibitory, which can prevent c-KIT activation in the absence of extracellular ligand. As the ligand, such as a stem cell factor, binds to the extracellular domain, the Kit receptors dimerize to each other, resulting in autophosphorylation of the tyrosine kinase domains and activation.[23],[24] Once activated, c-KIT can initiate the activation of a variety of downstream pathways, including the MAPK/MEK and PI3K/AKT pathways, which play important roles in cancer development. The activation of c-Kit mutations in the juxtamembrane and other domains has been considered as an oncogene and also a therapeutic target in various tumors.[25],[26]

Cell proliferation rate can be regulated by the KIT/MAPK/MEK signaling pathway. The expression of the c-KIT mutation induces Ki67, and it was found in the primary tumors of patients with metastatic OMM. The Ki67 expression indicates an increase in cell proliferation rate. Thus, c-Kit mutations may result in poor prognosis of metastatic OMM.[27] Patients with c-Kit mutations in exon 11 (encodes the juxtamembrane domain) and exon 13 (encodes the tyrosine kinase domain) have been shown to have a shorter prognostic rate compared with patients with other mutations.[28],[29],[30]

A previous study reported that c-KIT expression was 96% in primary melanomas, whereas its expression was 55% in metastatic melanomas. Another study showed a possible role of c-KIT in some types of melanoma, such as mucosal melanomas (21% KIT mutations, and 61% KIT overexpression), acral cutaneous melanomas (11% KIT mutations, and 75% c-Kit overexpression), and cutaneous melanomas on the skin with chronic sun damage (17% KIT mutations, and 100% c-Kit overexpression). Cytoplasmic c-KIT staining was significantly correlated with poor survival in patients.[31],[32]

The c-Kit mutations might act as adverse prognostic factors of metastatic OMMs. The c-Kit plays the role of an important target in the research of molecular therapy. Through the MAPK/MEK and PI3K/AKT pathways, the c-Kit plays an important role in cancer development. The c-Kit mutations have been resulting in a loss of heterozygosity at 12p13, and a loss of p27KIP1 protein has been detected. The activation of c-Kit mutations in the juxtamembrane and other domains has been considered as an oncogene and also a therapeutic target in various tumors.[33],[34]

Histological diagnosis might be difficult, especially when biopsy specimens are not dimensionally sufficient and multiple biopsies are sometimes required. Despite this, the c-kit mutation might be an alternative for the early diagnosis of OMM. This finding could change early prevention in OMM. The use of new diagnostic methods, especially noninvasive ones, can be an incredible advantage in the pathological, clinical field. Further, for these patients, time is of fundamental importance in reducing mortality. The possibility of having a reliable, fast, and precise diagnostic tool can be an advantage for the clinician, who daily relates to patients.[35],[36] There is no limitation in this study; moreover, further research is needed to confirm additional pathways for the c-kit mutation.


  Conclusion Top


The c-Kit mutations act as adverse prognostic factors of metastatic OMMs. The c-Kit plays the role of an important target in the research of molecular therapy. The c-KIT inhibitor could benefit patients with metastatic OMM with c-Kit mutations.

Acknowledgments

Not applicable.

Financial support and sponsorship

The authors declare no financial supports and sponsorship.

Conflicts of interest

The authors declare no conflicts of interest.

Authors’ contributions

NRPG contributes formal analysis, investigation, resources, and writing. ARPG contributes original draft, conceptualization, methodology, data curation and writing – review and editing. HMP contributes conceptualization, formal analysis, data curation and writing – review and editing.

Ethical policy and Institutional Review board statement

Not applicable.

Patient declaration of consent

Not applicable.

Data availability statement

The data used to support the findings can be searched ion PubMed (from January 1999 to October 2019), PubMed Advanced Search, Cochrane, EBSCO, and MEDLINE.

 
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    Figures

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