Treatment of Metastatic Melanoma Patients Bearing c-Kit Mutation Using Imatinib Mesylate

c-Kit Aberration in Melanoma and the Ethnic Differences

The c-Kit gene encodes a type III transmembrane receptor tyrosine kinase (RTK), also known as CD117, that plays a role in cell survival, proliferation, and differentiation. c-Kit is a cell surface receptor consisting of an extracellular domain, a transmembrane domain (coded by exon 10), a cytoplasmic domain consisting of a juxtamembrane domain (coded by exon 11), and two intracellular tyrosine kinase domains (coded by exons 12–21) ( ). c-Kit has been identified as a proto-oncogene and regarded as a target in cancer treatments, including gastrointestinal stromal tumor (GIST), leukemia, and melanoma.

Molecular profiling of c-Kit in melanoma suggests that c-Kit aberration is different among subtypes of melanoma. c-Kit mutation and/or an increase in c-Kit copy numbers is/are more common in mucosal, acral, and CSD melanomas, whereas BRAF mutations are highly prevalent in non-CSD melanomas ( ). examined 102 primary melanomas and found mutations and/or copy number increases of c-Kit in 39% of mucosal melanomas, 36% of acral melanomas, and 28% of CSD melanomas, but no c-Kit mutation was found in non-CSD melanomas. reported that c-Kit mutation was detected in 23% of acral melanomas, 15.6% of mucosal melanomas, 7.7% of conjunctival melanomas, 1.7% of cutaneous melanomas, and 0% of choroidal melanomas when studying a cohort of 189 melanomas.

In Chinese melanoma patients examined in our center, c-KIT mutation profile was detected in 502 patients ( ). The overall incidence of somatic mutations within the c-Kit gene was 10.8% (54/502), and all subtypes of melanoma contained c-Kit mutations. The frequency of c-Kit mutations in the acral, mucosal, and CSD melanomas were 11.9% (23/193), 9.6% (16/167), and 20.7% (6/29), respectively. This may be the largest study ever performed for evaluation of the c-Kit mutation in melanoma. reported that the frequency of c-Kit mutations in a Japanese cohort, which mainly consisted of metastatic acral melanomas, was approximately l7%. These studies in Asian populations suggest that although acral and mucosal melanomas are more prevalent in Asian populations, the frequency of c-Kit mutations seems lower than in Caucasian patients. The possible reasons for the differences in c-Kit mutations between Asian and Caucasian populations are unclear, which may be attributed to geographic location that leads to subtype bias of melanoma or to the baseline characteristics of melanoma patients since more metastatic lesions are included in the studies of Asian patients. have revealed that c-Kit expression tends to be diminished in metastatic lesions. The L576P c-Kit mutation within exon 11 and K642E exon 13 are the most common c-Kit mutations in melanoma (~30–40% of mutations) ( ). Our study also showed the most frequent c-Kit mutations were L576P (9 cases) and K642E (5 cases) ( ). Moreover, for the first time, our study suggests that c-Kit aberrations (mutation plus amplification) adversely impact survival of melanoma patients.

Protein expression of c-Kit can be detected in the majority of mucosal melanomas (up to 91%) ( ) and also in a high percentage of cutaneous melanomas (up to 84%) ( ). The association between CD117 protein expression and c-Kit mutation in melanoma has been studied many times. found that eight of the nine anorectal melanomas were positive for CD117 expression, with only three samples showing strong expression (one sample contained the L576P c-Kit mutation). reported that 23% of anal melanomas showed a diffuse and strong reactivity to the antibody of CD117, and only 3 cases with L576P mutation were identified in a total of 20 cases tested. We examined CD117 expression in 502 melanoma patients. Among the 54 cases with c-Kit mutation, 24 cases (44.4%) were positive for CD117, which was not significantly different from the positive rate of CD117 (39.6%) detected in the overall population ( ). We also found that 68.8% (11/16) of mucosal melanomas with c-Kit mutation were positive for CD117, not significantly higher than those in acral melanomas (34.8%), CSD melanomas (16.7%), non-CSD melanomas (60.0%), and melanomas of unknown primary (25.0%). examined 40 cases of anorectal melanomas, 16 of them showed diffuse and strong expression of CD117, and one melanoma had weak and focal reactivity. The tumors harboring c-Kit mutation (one tumor with L576P mutation, one tumor with G562V and E583V double mutation, and the third with W557R mutation) showed diffuse and strong expression of CD117. These studies indicate that CD117 protein expression might not correlate with the mutation status of c-Kit, which is consistent with the conclusion by . They observed increased expression of CD117 in 33% of melanomas without detectable c-Kit mutation or without increases in copy numbers. In contrast, in the study by , three melanomas with c-Kit L576P mutation were strongly immunopositive for CD117. They reported that there was a higher expression of CD117 in anorectal melanomas harboring a potentially gain-of-function c-Kit mutation than that in the tumors without c-Kit mutations.