Analysis of c-KIT expression and KIT gene mutation in human mucosal melanomas (2024)

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Analysis of c-KIT expression and KIT gene mutation in human mucosal melanomas (1)

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Br J Cancer. 2008 Dec 9; 99(12): 2065–2069.

Published online 2008 Nov 18. doi:10.1038/sj.bjc.6604791

PMCID: PMC2607233

PMID: 19018266

I Satzger,1,* T Schaefer,1 U Kuettler,1 V Broecker,2 B Voelker,1 H Ostertag,3 A Kapp,1 and R Gutzmer1

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Recent data suggested an increased frequency of KIT aberrations in mucosal melanomas, whereas c-KIT in most types of cutaneous melanomas does not appear to be of pathogenetic importance. However, studies investigating the status of the KIT gene in larger, well-characterised groups of patients with mucosal melanomas are lacking. We analysed 44 archival specimens of 39 well-characterised patients with mucosal melanomas of different locations. c-KIT protein expression was determined by immunhistochemistry, KIT gene mutations were analysed by PCR amplification and DNA sequencing of exons 9, 11, 13, 17 and 18. c-KIT protein expression could be shown in 40 out of 44 (91%) tumours in at least 10% of tumour cells. DNA sequence analysis of the KIT was successfully performed in 37 patients. In 6 out of 37 patients (16%) KIT mutations were found, five in exon 11 and one in exon 18. The presence of mutations in exon 11 correlated with a significant stronger immunohistochemical expression of c-KIT protein (P=0.015). Among the six patients with mutations, in two patients the primary tumour was located in the head/neck region, in three patients in the genitourinary tract and in one patient in the anal/rectal area. In conclusion, KIT mutations can be found in a subset of patients with mucosal melanomas irrespective of the location of the primary tumour. Our data encourage therapeutic attempts with tyrosine kinase inhibitors blocking c-KIT in these patients.

Keywords: melanoma, mucosal, c-KIT, KIT, BRAF

Primary mucosal melanomas represent a rare subtype of melanomas that arise from melanocytic cells residing in mucous membranes in various anatomical regions. They account for approximately 1.2% of melanomas (Chang et al, 1998) and have mainly been described in the head and neck region, the genitourinary tract and the gastrointestinal tract.

Obviously, sun exposure does not play a role in mucosal melanoma, whereas it is a risk factor in cutaneous melanoma. A recent study described genetic differences between mucosal melanomas and cutaneous melanomas. In this study, four types of melanomas were differentiated, that is, mucosal melanomas, acral melanomas, melanomas on skin with chronic sun damage and melanomas on skin without chronic sun damage. Melanomas arising from skin without chronic sun damage, representing the major group of cutaneous melanomas, were shown to frequently harbour BRAF mutations, in particular the BRAF V600E mutation. The other melanoma types, including mucosal melanoma, had a high frequency of mutations of the KIT gene (Curtin et al, 2005, 2006). This finding is in particular intriguing as it may represent a rationale for a targeted therapy with specific tyrosine kinase inhibitors such as c-KIT blockers in mucosal melanomas. To further elucidate the role of c-KIT and BRAF in mucosal melanoma, we analysed these two targets in 39 patients with mucosal melanomas treated in our Department.

Materials and methods


Thirty nine patients with mucosal melanomas who were treated in our Department (Skin Cancer Center Hannover) from 1996 to 2007 were retrospectively analysed. A total of 44 archival formalin-fixed and paraffin-embedded tissue samples (35 primary melanomas, 4 lymph node metastases, 2 skin metastases and 3 local recurrences) were accessible for analysis in this study.

Immunohistopathologic evaluation of c-KIT expression

Highly sensitive immunohistochemistry for c-KIT with a murine monoclonal antibody (clone p145, dilution 1 : 100, DakoCytomation, Hamburg, Germany) was performed as described earlier (Satzger et al, 2008) and immunohistochemical stainings were evaluated semiquantitatively. The numbers of positively labelled melanoma cells were scored as follows: 0 for less than 10% positive cells, 1 (+) for 10–25% positive cells, 2 (++) for 26–50% positive cells, 3 (+++) for 51–75% and 4 (++++) for 76–100% positive cells. We did not differentiate between cytoplasmatic and membranous staining as we did not observe isolated surface staining and earlier studies showed cytoplasmatic staining along with membranous staining in melanoma cells positive for c-KIT (Pereira et al, 2005; Giehl et al, 2007; Rivera et al, 2008).

Mutational analysis of KIT

Tumour cells were isolated from paraffin-embedded tissue (either primary tumour, lymph node metastases, skin metastases or local recurrences), if necessary by micrographic dissection using the PALM Laser-MicroBeam System (PALM Wolfratshausen, Germany). DNA extraction was performed with the DNA extraction kit from Qiagen (Hilden, Germany) following the instructions of the manufacturer. Exons 9, 11, 13, 17, 18 of KIT were amplified by LightCycler PCR using specific primers as described in the literature (Tarn et al, 2005; Curtin et al, 2006). Polymerase chain reaction products were DNA sequenced using an ABI Prism 3700 DNA Analyzer (SeqLab, Göttingen, Germany).

Mutational analysis of BRAF

To detect the BRAF V600E mutation a LightCycler fluorescence resonance energy transfer (FRET) assay with two fluorescent hybridisation probes was performed as described earlier (Hay et al, 2007). Real-time PCR was performed by using LightCycler FastStart DNA Master HybProbe (Roche Diagnostics GmbH, Mannheim, Germany). Post amplification fluorescent melting curve analysis was performed by gradual heating of the samples at a rate of 0.2°C per second from 45 to 95°C. Fluorescent melting peaks were determined by plotting of the negative derivative of fluorescence with respect to temperature.

All PCR products that showed deviation from the Wt (wild-type) genomic DNA melting peak as well as from the positive control samples were confirmed by direct sequencing of exon 15 of the BRAF gene (SequiServe, Vaterstetten, Germany).

Statistical analyses

The software SPSS 13.0 was used for statistical analyses. Kaplan–Meier tests and unpaired t-tests were performed.


c-KIT expression was determined in 44 tissue samples, 35 primary mucosal melanomas, 4 lymph node metastases, 2 skin metastases and 3 local recurrences (Table 1). In all, 31 out of 35 (89%) primaries, 4 out of 4 (100%) lymph node metastases, 2 out of 2 (100%) skin metastases and 3 out of 3 (100%) local recurrences were positive for c-KIT (Figure 1A). c-KIT protein expression could be detected in 18 out of 18 (100%) mucosal melanomas located in the head/neck area, 7 out of 8 (86%) in the anal/rectal tract, 8 out of 11 (73%) in the genitourinary tract and 2 out of 2 (100%) in other locations. Score 1+ was determined in 8 out of 44 samples (18%), score 2+ in 7 out of 44 (16%) samples, score 3+ in 9 out of 44 (20%) samples and score 4+ in 16 out of 44 samples (36%). The degree of the c-KIT expression did not correlate with disease-free survival (P=0.44) and overall survival (P=0.82) by Kaplan–Meier analysis during a follow-up of 31.1 months (mean) and 21.1 months (median, minimum 2.8 months, maximum 151.6 months). During that follow-up period, 20 patients suffered from melanoma recurrence and 14 patients died due to melanoma metastases.

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Figure 1

(A) Immunhistochemical staining of c-KIT in primary mucosal melanoma showing strong positive membranous and cytoplasmatic labelling (++++) of primary melanoma (a), lymph node metastases (b) and skin metastases (c) of patient 27 (magnification × 100) and, weak and inhom*ogeneous labelling (+) of primary melanoma (d) of patient 18 (magnification × 100). (B) KIT genotyping shows a deletion 579 in exon 11 (patient 24). The upper curve depicts the KIT exon 11 forward sequence and the lower curve depicts the wild-type sequence. (C) Melting curve analysis of five patients with mucosal melanomas. Melting curve peaks at 64.7°C from BRAF wild type (Patient nos.1, 3 and 4, corresponding to patients 1, 3 and 4 in Table 1) and melting curve peak at 60.6°C from BRAF V600E heterozygous mutation (cases 2 and 5, corresponding to cases 16 and 38 in Table 1).

Table 1

Characterisation of patients, expression of c-KIT by immunohistochemistry (IHC), mutational status of KIT and BRAF in mucosal melanoma, clinical follow-up

CaseAge (years)GenderLocationTissue sampleIHC c-KITKIT statusBRAF statusFollow-up
180FHead/NeckPM++++WtWtProgression in 9 months
244MHead/NeckPM+++Exon 11, K550NWtProgression in 5 months
369FHead/NeckPM+NAWtDeath due to melanoma in 74 months
475MHead/NeckPM+++WtWtDeath due to melanoma in 8 months
552MHead/NeckPM+++WtNANo progression
675MHead/NeckPM+++WtWtProgression in 27 months
759MHead/NeckPM++++NANAProgression in 8 months
877MHead/NeckLR+WtNAProgression in 24 months
980FHead/NeckPM++++WtWtNo progression
1064MHead/NeckPM++++WtWtNo progression
1168FHead/NeckPM+++WtNADeath due to melanoma in 11 months
1272MHead/NeckPM++WtWtDeath due to melanoma in 25 months
1378MHead/NeckPM++++WtWtProgression in 11 months
1494MHead/NeckPM++++Exon 11, W557RWtDeath due to melanoma in 7 months
1563FHead/NeckPM++WtWtDeath due to melanoma in 5 months
1657MHead/NeckPM+WtheteroDeath due to melanoma in 6 months
1759MHead/NeckPM+++WtWtNo progression
1880FHead/NeckPM+WtWtNo progression
1922FGenital tractPMnegativeNANANo progression
2059FGenital tractPM+WtNAProgression in 33 months
2172FGenital tractPM++++WtNANo progression
2265FGenital tractPM+++WtWtDeath due to melanoma in 32 months
2386FGenital tractPMnegativeWtWtNA
2465FGenital tractPM++++Exon 11, 579delWtNo progression
2550FGenital tractPM++Exon 18, I841VWtNo progression
2681FGenital tractPMnegativeWtNADeath due to melanoma in 37 months
2776FGenital tractPM++++NANADeath due to melanoma in 13 months
SM++++Exon 11, L576PNA
LN++++Exon 11, L576PNA
2865FGenital tractLR+++WtWtDeath due to melanoma in 11 months
2974FUrinary tractPM++++NAWtDeath due to melanoma in 114 months
3061MAnal/rectalPM++++WtNADeath due to melanoma in 51 months
3165MAnal/rectalPMnegativeWtNADeath due to melanoma in 25 months
3265FAnal/rectalPM+++WtWtDeath due to melanoma in 16 months
3373MAnal/rectalPM++WtWtProgression in 13 months
3466MAnal/rectalPM+WtWtDeath due to melanoma in 24 months
3555MAnal/rectalLN++WtNAProgression in 26 months
3679FAnal/rectalPM++++Exon 11, L576PWtProgression in 9 months
3764FAnal/rectalPM+WtNADistant metastasis at diagnosis
3852FConjunctivaLN+WtheteroDeath due to melanoma in 137 months
3953FPleuraPM++WtheteroProgression in 3 months

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hetero=heterozygous, LN=lymph node metastasis; LR=local recurrence, NA=not available, PM=primary melanoma, SM=skin metastasis, Wt=wild-type.

IHC-assessment: negative for less than 10% positive cells, +for 10–25% positive cells, ++ for 25–50% positive cells, +++ for 50–75% and ++++ for 75 to 100% positive cells.

Alterations in the KIT gene were observed in 6 out of 37 (16%) patients, five in exon 11 and one in exon 18 (Figure 1B). Two patients suffered from mucosal melanomas of the head/neck region, three patients from mucosal melanomas located in the genitourinary tract and one patient from mucosal melanoma located in the anal/rectal tract. In one patient (case 27) the KIT mutation could be detected both in lymph node metastases and in skin metastases. Among the five tumours with KIT gene mutation of exon 11, four (80%) tumours showed strong (++++) and one showed (20%) high (+++) c-KIT protein expression (Figure 1A). In contrast, tumours without mutation in exon 11 had significantly lower c-KIT expression (3 out of 32 negative, 7 out of 32 (+), 7 out of 32 (++), 8 out of 32 (+++), 7 out of 32 (++++), P=0.015).

In 3 out of 27 (11%) mucosal melanomas (located in head/neck area, pleura and conjunctiva, respectively) the BRAF V600E mutation could be detected (Table 1, Figure 1C).


A recent report showed a possible role of c-KIT in subsets of melanoma, in particular, mucosal melanomas (21% KIT mutations, 61% c-KIT overexpression), acral cutaneous melanomas (11% KIT mutations, 75% c-KIT overexpression) and cutaneous melanomas on skin with chronic sun damage (17% KIT mutations, 100% c-KIT overexpression) (Curtin et al, 2006). This suggests that c-KIT might be of pathogenetic relevance and therefore a therapeutic target in these subtypes of melanoma. In contrast, KIT mutations are rarely found in the major subtype of cutaneous melanoma originating from skin without chronic sun damage (Curtin et al, 2006) and unselected cutaneous melanomas (2 out of 100 in Willmore-Payne et al (2005); 1 out of 39 in Went et al (2004)). Moreover, therapeutic phase II studies with the c-KIT blocker imatinib in unselected melanoma patients without known KIT mutation status were disappointing (Ugurel et al, 2005; Wyman et al, 2006; Becker et al, 2007).

The aim of this study was to further elucidate c-KIT alterations in our well-characterised group of patients with mucosal melanomas that might support the role of c-KIT as a new therapeutic target in this subgroup of melanoma. The successful genetic analysis of KIT in 37 patients revealed mutations in 6 patients (16%). We could show KIT mutations in 2 out of 12 mucosal melanomas from head/neck, 3 out of 11 from the genitourinary tract and 1 out of 8 from the anal/rectal tract. This is consistent with the findings of Antonescu et al and Rivera et al who detected mutations of the KIT gene in 3 out of 20 (15%) and 4 out of 18 (22%) patients with mucosal melanomas of the anal region and oral cavity, respectively (Antonescu et al, 2007; Rivera et al, 2008). Thus, KIT mutations occur in up to 20% of mucosal melanomas irrespective of the location of the primary tumour.

The majority of KIT mutations in mucosal melanomas (11 out of 16 tumours in Curtin et al (2006), 3 out of 3 in Antonescu et al (2007), 4 out of 4 in Rivera et al (2008) and 5 out of 6 in our study) were detected in the juxtamembrane region of KIT encoded by exons 11 and 13, presumably resulting in the activation of c-KIT.

The L576P und W557R mutations of our patients have already been described both in mucosal melanomas and gastrointestinal stromal tumours (GIST) (Antonescu et al, 2004, 2007; Rivera et al, 2008). Deletions covering the 579 position (such as in our patient 24) have also been frequently described in GIST (Tarn et al, 2005). The K550N mutation found in our patient 2 has, to our knowledge, not been described yet. However, other alterations in the proximal part of exon 11 at codons 550–562 have been reported frequently in GIST (Lasota et al, 1999; Longley et al, 2001).

Thus, the minor subgroup of patients with mucosal melanomas and activating KIT mutations might be susceptible to therapeutic c-KIT blockade. This is supported by findings in GIST, which show KIT mutations in 75–80%, and respond significantly better to a therapy with the c-KIT inhibitor imatinib than tumours without KIT mutations (Heinrich et al, 2003). Therefore, therapeutic c-KIT blockade could be considered for the treatment of patients with mucosal melanomas and an activating KIT mutation. This is supported by two case reports published very recently of single patients suffering from metastasising anal melanoma that harboured a KIT mutation in exon 11 and exon 13, respectively. These patients were successfully treated with the c-KIT blocker imatinib (Hodi et al, 2008; Lutzky et al, 2008).

c-KIT protein expression could be observed in 91% of our primary mucosal melanomas, which is similar to the rates reported in other series of primary mucosal melanomas of the anal/rectal tract (12 out of 16 in Chute et al, 2006) and oral cavity (16 out of 18 in Rivera et al, 2008), respectively. However, Antonescu et al (2007) reported lower number (6 out of 26 (23%)) of c-KIT positivity in mucosal melanomas of the anal/rectal tract. In addition, cutaneous melanomas have been reported to express c-KIT by immunohistochemistry in 22.8% (Potti et al, 2003) up to 84% (Giehl et al, 2007) of the cases. The high range between these studies is being explained with the different qualities of immunohistochemistry. Thus, c-KIT protein expression appears to be in a similar range in mucosal melanomas and cutaneous melanomas. In line with this, Giehl et al could find no differences of the c-KIT expression in melanomas with sun exposure compared with melanomas without sun exposure (Giehl et al, 2007). In contrast to metastatic melanoma from primary cutaneous melanoma, where the c-KIT expression is decreased (Montone et al, 1997; Shen et al, 2003), we could observe c-KIT expression in 9 out of 9 metastases of primary mucosal melanoma. Similarly, Antonescu et al detected c-KIT reactivity in 6 out of 6 metastases from their anal mucosal melanomas (Antonescu et al, 2007). Furthermore, in agreement with earlier studies we could not show a prognostic relevance of the c-KIT protein expression in mucosal melanomas (Chute et al, 2006).

We could observe a significant higher immunohistochemical expression of c-KIT in mucosal melanomas that harbour a potentially activating KIT mutation as compared with tumours without KIT mutation. A similar correlation has also been found for anal melanomas (Antonescu et al, 2007) and melanomas of the oral cavity (Rivera et al, 2008).

Thus, immunohistochemistry might be a useful tool to screen for patients that are subjected to KIT mutation analysis. However, immunohistochemistry might not be sufficient to detect tumours with mutations susceptible for c-KIT blockade, as overexpression of c-KIT can also occur in tumours without mutation. This is illustrated by the report of three patients with metastatic melanoma and strong immunohistochemical c-KIT expression who did not respond to a therapy with the c-KIT blocker imatinib (Alexis et al, 2005).

BRAF mutations were rarely identified in 3 out of 27 (11%) patients in our series, similarly to other studies with patients suffering from mucosal melanomas who reported 1 out of 17 (Cohen et al, 2004) and 0 out of 13 (Edwards et al, 2004), respectively, whereas the majority of cutaneous melanomas on skin without chronic sun-induced damage harbour BRAF V600E mutations (Curtin et al, 2005). It is interesting to note that one of our patients with a BRAF mutation suffered from melanoma located in an UV-exposed area of the conjunctiva. In line with this, Gear et al (2004) reported BRAF mutations in 5 out of 22 patients with conjunctival melanomas.

In conclusion, our study supports the finding that KIT mutations presumably activating the tyrosine kinase activity of c-KIT can be found in a subgroup of patients with mucosal melanomas irrespective of the origin of the primary tumour. This encourages clinical studies with c-KIT blockers in patients with mucosal melanomas and appropriate KIT mutations. Immunohistochemistry for c-KIT expression might be a useful tool to screen for patients who are subjected to mutational analysis but cannot replace genetic analysis.


This study was supported by Hannelore-Munke research grant of Hannover Medical School (Hannover, Germany).


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Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

Analysis of c-KIT expression and KIT gene mutation in human mucosal melanomas (2024)


What is c-KIT mutation analysis? ›

c-KIT Mutation Analysis. Molecular. Bi-directional sequencing of KIT exons 8, 9, 11, 13 and 17 for detection of activating mutations including the common mutation D816V. For solid tumors, tumor enrichment is performed before extraction. In hematological disease, testing may be performed on plasma to increase ...

What are the genetic mutations in mucosal melanoma? ›

The most frequent mutations in mucosal melanoma were in SF3B1 (27%), KIT (18%), and NF1 (17%), a pattern that is distinct from cutaneous melanomas. In addition, there were genetic differences observed based upon the site of origin of the mucosal melanoma.

What is a KIT mutation in melanoma? ›

KIT exon 11, exon 13 and exon 17 mutations correlate with c-KIT- activating mutations. KIT mutations in melanomas are associated with favorable response to imatinib, and probably to other tyrosine kinase KIT inhibitors. KIT mutations are most frequently observed in mucosal and acral melanomas.

What are the symptoms of the kit gene mutation? ›

In systemic mastocytosis, the excess mast cells lead to an increased immune response and signs and symptoms similar to an allergic reaction, such as skin redness and warmth (flushing), nausea, abdominal pain, nasal congestion, low blood pressure (hypotension), and headache.

What is the most common KIT mutation? ›

KIT mutations in exon 11 are the most common mutation in GISTs and are identified in approximately 70% of cases. As a group, exon 11 mutations portend a high risk of relapse after surgical resection.

What is c-kit a marker for? ›

Measuring the amount of c-kit in tumor tissue may help diagnose cancer and plan treatment. C-kit is a type of receptor tyrosine kinase and a type of tumor marker. Also called CD117 and stem cell factor receptor.

What is the most common gene mutation in melanoma? ›

The most common change in melanoma cells is a mutation in the BRAF oncogene, which is found in about half of all melanomas. Other genes that can be affected in melanoma include NRAS, CDKN2A, and NF1. (Usually only one of these genes is affected.)

How do you know if melanoma is genetic? ›

The genetic test for melanoma can tell you whether you have a mutation (change) in a gene that gives you an increased risk of developing melanoma. These mutations are passed down in the family tree.

What genetic syndrome is associated with malignant melanoma? ›

An autosomal recessive disease, called xeroderma pigmentosum (XP), is associated with increased BCC, SCC, and melanoma risks.

What is the most commonly mutated gene in melanoma? ›

The gene most frequently altered is the tumor suppressor merlin (NF2); a mutation in this gene is present in approximately 45% of meningiomas.

How do you get mucosal melanoma? ›

Researchers believe mucosal melanoma to be caused by a combination of genetic and environmental factors. Unlike cutaneous melanoma, and based on the locations where mucosal melanoma arises, it is not caused by exposure to UV radiation from the sun.

What is the gene expression test for melanoma? ›

DecisionDx-Melanoma is a gene expression profile test that provides comprehensive, personalized results to guide risk-aligned management decisions for patients with stage I-III cutaneous melanoma.

How do you treat c-kit mutations? ›

Imatinib mesylate is a derivative of 2-phenyaminopyrimidine that acts as a small molecule inhibitor targeting RTKs. It is considered the first-line treatment for GIST patients with c-KIT or PDGFRA mutations.

How to test for KIT mutation? ›

DNA is extracted and purified from fresh blood, bone marrow aspirate, paraffin-embedded bone marrow biopsy, clot or other tissue (e.g. skin, GI biopsy). Samples from adult patients are screened for the D816V mutation by real-time allele-specific PCR that includes an internal positive control for DNA quality.

What does a c-kit test for? ›

Test Details

c-KIT and its ligand stem cell factor have a key role in survival, proliferation, differentiation and functional activation of hematopoietic progenitor cells. c-KIT mutations are reported in the majority of systemic mastocytosis cases.

Are c-kit mutations inherited? ›

Somatic mutations, which lead to sporadic GISTs, are present only in the tumor cells and are not inherited. Less commonly, KIT gene mutations that increase the risk of developing GISTs are inherited from a parent, which can lead to familial GISTs.

What is c-kit antibody? ›

A human monoclonal antibody targeting the stem cell factor receptor (c-Kit) blocks tumor cell signaling and inhibits tumor growth.

Is c-kit a tumor suppressor gene? ›

Thus, c-Kit acts both as a proto-oncogene via its kinase activity and as a tumor suppressor via its dependence receptor activity.

What is the role of CKIT? ›

c-kit is a classical proto-oncogene that encodes a receptor tyrosine kinase (RTK) that responds to stem cell factor (SCF). C-KIT signaling is a critical regulator of cell proliferation, survival, and migration and is implicated in several physiological processes, including pigmentation, hematopoiesis, and gut movement.

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