KIT Gene Mutations and Copy Number in Melanoma Subtypes

Abstract

Purpose:We recently identified a KITexon11mutation in an anorectal melanoma of a patient who had an excellent response to treatment with imatinib.To determine the frequency of KIT mutations across melanoma subtypes, we surveyed a large series of tumors. Experimental Design: One hundred eighty-nine melanomas were screened for mutations in KIT exons 11, 13, and 17. KIT copy number was assessed by quantitative PCR. A subset of cases was evaluated for BRAF and NRAS mutations. Immunohistochemistry was done to assess KIT (CD117) expression. Results: KIT mutations were detected in 23% (3 of 13) of acral melanomas, 15.6% (7 of 45) of mucosal melanomas, 7.7% (1 of 13) of conjunctival melanomas, 1.7% (1 of 58) of cutaneous melanomas, and 0% (0 of 60) of choroidal melanomas. Almost all the KIT mutations were of the type predicted to be imatinib sensitive.There was no overlap with NRAS mutations (11.1% of acral and 24.3% of mucosal tumors) or with BRAF mutations (absent in mucosal tumors). Increased KIT copy number was detected in 27.3% (3 of 11) of acral and 26.3% (10 of 38) of mucosal melanomas, but was less common among cutaneous (6.7%; 3 of 45), conjunctival (7.1%; 1 of 14), and choroidal melanomas (0 of 28). CD117 expression, present in 39% of 105 tumors representing all melanoma types, did not correlate with either KIT mutation status or KIT copy number. Conclusions: Our findings confirm that KIT mutations are most common in acral and mucosal melanomas but do not necessarily correlate with KIT copy number or CD117 expression. Screening for KIT mutations may open up new treatment options for melanoma patients.

c-Kit mutants require hypoxia-inducible factor 1α to transform melanocytes

“…Discussion c-Kit mutations have recently been identified in certain subsets of melanoma, such as acral, mucosal and skin with sun-induced damage Beadling et al, 2008), but the biological significance of these mutations remains unclear. We have shown here for the first time that c-Kit mutants use a different molecular mechanism than N-Ras or B-Raf oncogenes to transform melanocytes.…”

“…The presence of a mild hypoxic environment in the skin has already been described (Bedogni et al, 2005), but it remains to be determined whether hypoxia is elevated in the skin located at the extremities of the hands and feet or in the mucosa where acral and mucosal melanoma develop. This strict dependency of c-Kit mutants on the microenvironment could explain the low frequency of c-Kit mutations in cutaneous melanoma (around 2%) Beadling et al, 2008). Interestingly, HIF-1a has also been identified as a target for microphthalmia-associated transcription factor (MITF) (Busca et al, 2005).…”

“…One hypothesis was that c-Kit signaling was important for melanocyte differentiation, and therefore, loss of its expression was a required step in the course of tumor progression. However, the role of c-Kit in melanomagenesis is likely to be more complex as a subset of melanoma has been found to maintain c-Kit overexpression, even in metastatic lesions, and mutations activating c-Kit have recently been identified in some melanoma Beadling et al, 2008). Acral and mucosal melanoma are subsets of melanoma presenting mutations in the c-Kit gene.…”

KIT mutations in ocular melanoma: frequency and anatomic distribution

“…Subsequently, others confirmed the presence of KIT mutations in the invasive portion of primary malignant melanomas and in their metastatic deposits. [7][8][9] These findings suggested that targeted molecular therapy with tyrosine kinase inhibitors could be successful for melanoma, which is a notoriously difficult malignancy to treat. Indeed, promising results have emerged from clinical studies investigating the use of imatinib for melanoma patients with confirmed KIT-activating mutations.…”

“…Acral, mucosal, and chronic sun damaged skin melanomas have been shown to harbor KIT mutations while non-chronic sun damaged skin melanomas generally do not since they are often characterized by BRAF or NRAS mutations. [7][8][9]14,15 The frequency of KIT-activating mutations in specific melanoma subtypes is relatively low with reports of 15% for acral, 19% for mucosal, and 17% for chronic sun damaged skin melanomas. 15,16 Ocular melanoma, although a rare melanoma subtype, does account for the majority of all intraocular malignancies.…”