Expression of the c-kit receptor in choroidal melanomas

Mouriaux, Frédéric; Kherrouche, Zoulika; Maurage, Claude‐Alain; Demailly, François-Xavier; Labalette, P.; Saule, Simon

doi:10.1097/00008390-200304000-00008

Cited by 35 publications

(41 citation statements)

References 25 publications

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“…Indeed, clinical studies using imatinib in melanoma patients with confirmed KIT-activating mutations have yielded promising results. [10][11][12][13] Although it is arguably premature, the reported high frequency of KIT overexpression in ocular melanoma (63-91%) [17][18][19][20][21][22] has led to an interest in the use of imatinib therapy for this melanoma subtype. In initial studies, however, overexpression of KIT protein in ocular melanoma does not appear to imply response to imatinib.…”

Section: Discussionmentioning

confidence: 99%

“…Arising from melanocytes of the choroid, iris, ciliary body, and conjunctiva, ocular melanomas have been reported to express KIT (CD117) at frequencies between 63 and 91%. [17][18][19][20][21][22] KIT mutations, however, have only been reported in one conjunctival tumor. 8 Given the low frequency of KIT mutations (o1%) in ocular melanoma, it is not surprisingly that recent studies have failed to demonstrate the clinical efficacy for imatinib mesylate therapy in unselected patients.…”

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KIT mutations in ocular melanoma: frequency and anatomic distribution

et al. 2011

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KIT mutations are known to occur in B15% of chronic sun damaged cutaneous, mucosal, and acral melanomas. Melanomas with demonstrated activating mutations in KIT or platelet-derived growth factor receptor A (PDGFRA) may benefit from treatment with tyrosine kinase inhibitors. Currently, the limited data regarding KIT mutational status in ocular melanoma suggest that activating mutations are extremely rare. PDGFRA mutational status in ocular melanoma has not been determined. Seventy-five ocular melanomas (53 choroidal, 6 iris, 11 ciliary body, and 5 conjuctival) were selected from the files of the Department of Ophthalmology. High-resolution melting curve analysis and sequencing were performed to detect mutations in KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18. Results of mutational analysis were correlated with anatomical site and KIT (CD117) immunohistochemistry. Eight of 75 (11%) ocular melanomas contained mutations in either the KIT or PDGFRA gene. Five of 53 (9%) choroidal melanomas were associated with mutations (KIT exon 11 ¼ 3; KIT exon 17 ¼ 1; PDGFRA intron 18 ¼ 1). Two of six (33%) iris melanomas and a single (9%) ciliary body melanoma harbored KIT exon 11 mutations. No mutations were identified in conjunctival melanomas. The distribution of KIT and PDGFRA mutations by ocular melanoma anatomical site did not reach statistical significance (P ¼ 0.393) CD117 positivity was not predictive of KIT mutational status as only 6 of 58 (10%) CD177-positive tumors harbored KIT mutations. In addition, a KIT exon 17 mutation was identified in one CD117-negative tumor. KIT and PDGFRA mutations do occur in ocular melanomas at a frequency (11%) that is similar to acral and mucosal melanomas. Limited correlation of CD117 positivity with mutational status suggests that all ocular melanomas should undergo mutational analysis to determine if imatinib therapy is appropriate.

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confidence: 99%

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KIT mutations in ocular melanoma: frequency and anatomic distribution

et al. 2011

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“…We have demonstrated that c-Kit is activated by exogenous SCF during normal uveal melanocyte (NUM) proliferation and probably also during pathogenic bilateral and diffuse uveal cell proliferation (34). We have also shown that c-Kit is expressed in 75% of primary choroidal melanomas (35). Mitotic activity and c-Kit immunoreactivity are positively correlated, suggesting that c-Kit is involved in the transformation of normal uveal melanocytes into tumor cells (35).…”

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confidence: 88%

“…We have also shown that c-Kit is expressed in 75% of primary choroidal melanomas (35). Mitotic activity and c-Kit immunoreactivity are positively correlated, suggesting that c-Kit is involved in the transformation of normal uveal melanocytes into tumor cells (35). However, the roles of SCF/ c-Kit and of the downstream intracellular signaling pathway have been evaluated during the transformation of normal uveal melanocytes.…”

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confidence: 94%

Roles of Stem Cell Factor/c-Kit and Effects of Glivec®/STI571 in Human Uveal Melanoma Cell Tumorigenesis

Lefevre

Glotin

Calipel

et al. 2004

Journal of Biological Chemistry

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The B-Raf V599E -mediated constitutive activation of ERK1/2 is involved in establishing the transformed phenotype of some uveal melanoma cells (Calipel, A., Lefevre, G., Pouponnot, C., Mouriaux, F., Eychene, A., and Mascarelli, F. (2003) J. Biol. Chem. 278, 42409 -42418). We have shown that stem cell factor (SCF) is involved in the proliferation of normal uveal melanocytes and that c-Kit is expressed in 75% of primary uveal melanomas. This suggests that the acquisition of autonomous growth during melanoma progression may involve the SCF/c-Kit axis. We used six human uveal melanoma tumor-derived cell lines and normal uveal melanocytes to characterize the SCF/c-Kit system and to assess its specific role in transformation. We investigated the possible roles of activating mutations in c-KIT, the overexpression of this gene, and ligand-dependent c-Kit overactivation in uveal melanoma cell tumorigenesis. Four cell lines (92.1, SP6.5, Mel270, and TP31) expressed both SCF and c-Kit, and none harbored the c-KIT mutations in exons 9, 11, 13, and 17 that have been shown to induce SCF-independent c-Kit activation. Melanoma cell proliferation was strongly inhibited by small interfering RNA-mediated depletion of c-Kit in these cells, despite the presence of V599E B-Raf in SP6.5 and TP31 cells. We characterized the signaling pathways involved in SCF/c-Kit-mediated cell growth and survival in normal and tumoral melanocytes and found that constitutive ERK1/2 activation played a key role in both the SCF/c-Kit autocrine loop and the gain of function of V599E B-Raf for melanoma cell proliferation and transformation. We also provide the first evidence that Glivec®/STI571, a c-Kit tyrosine kinase inhibitor, could be used to treat uveal melanomas.

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“…Notably, UM was not included in the abovementioned study analyzing KIT activation in melanoma (6). This is particularly puzzling, as it has been shown that 75% of primary UM exhibited KIT positivity with a significant positive association with mitotic activity (8).…”

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Overexpression of the KIT/SCF in Uveal Melanoma Does Not Translate into Clinical Efficacy of Imatinib Mesylate

Hofmann

Kauczok-Vetter

Houben

et al. 2008

Clinical Cancer Research

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Purpose: Recently, gene amplification and overexpression of KITas well as activating mutations in the KIT gene have been described to occur in certain subsets of melanoma. These findings suggest KITas a potential target for therapy with imatinib mesylate in these melanomas. To date, data on the KITstatus in uveal melanoma (UM) is limited. Experimental Design: We analyzed the expression of the KIT protein (CD117, c-kit) and its ligand, stem cell factor (SCF), in primary and metastatic UM. Results: By immunohistochemistry, SCF-positive tumor cells (>90%) were detectable in 43% of primary UM and in 58% of UM metastases. Strong expression of KIT (>90%) in tumor cells was present in 55% of primary UM and in 76% of UM metastases.This overexpression of both KITand SCF suggests the clinical application of imatinib mesylate in metastatic UM. This notion was tested in a clinical study using Simon's two-stage design. Patients received imatinib (600 mg p.o. daily) until progress or unacceptable toxicities. The trial did not enter stage II as no objective response was observed in the first group. This observation prompted further molecular analysis, which revealed no mutations in the genomic sequence of KIT in exons 11, 13, 17, and 18. Moreover, the mitogen-activated protein kinase pathway was not activated in any of the tumors as measured by ERK phosphorylation. Conclusions: These results show the lack of clinical effectiveness of imatinib in UM, which was originally anticipated based on the high levels of KITand SCF expression.

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Expression of the c-kit receptor in choroidal melanomas

Cited by 35 publications

References 25 publications

KIT mutations in ocular melanoma: frequency and anatomic distribution

KIT mutations in ocular melanoma: frequency and anatomic distribution

Roles of Stem Cell Factor/c-Kit and Effects of Glivec®/STI571 in Human Uveal Melanoma Cell Tumorigenesis

Overexpression of the KIT/SCF in Uveal Melanoma Does Not Translate into Clinical Efficacy of Imatinib Mesylate

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