Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

Abstract

Merkel cell carcinoma is a rare and aggressive form of skin cancer of neuroendocrine origin. Its treatment involves wide excision and radiotherapy but no effective therapy exists for advanced disease. Upregulation of the platelet-derived growth factor receptor family of tyrosine kinases, PDGFRA and KIT, has a crucial role in cancer development. Several studies have shown expression of the tyrosine kinase receptor KIT (CD117) in Merkel cell carcinoma. In this study, we examined the expression and mutational status of KIT and PDGFRA in 14 primary and 18 metastatic Merkel cell carcinoma. The expression of KIT and PDGFRA and their respective ligands, stem cell factor (SCF) and PDGFA, was assessed by immunohistochemistry. In addition, we analyzed KIT exons 9, 11, 13 and 17, and PDGFRA exons 10, 12 and 18 for the presence of activating mutations. We found that only 53% of cases of Merkel cell carcinoma expressed KIT, which was mostly seen as diffuse weak staining, and SCF expression was observed only in 31% of cases. In contrast, 87 and 81% of cases expressed PDGFRA and PDGFA, respectively. We observed coexpression of SCF and KIT in only 5 of 32 cases (16%) whereas 25 of 31 cases (81%) showed coexpression of PDGFRA and its ligand PDGFA. While we documented silent mutations in exon 17 of KIT and exons 10, 12 and 18 of PDGFRA, we were not able to identify any known activating mutations. Our results indicate that there is no correlation between positive immunostaining and occurrence of activating mutations in KIT and PDGFRA. Moreover, the presence of KIT/SCF and PDGFRA/PDGFA coexpression in a proportion of cases may indicate an autocrine/paracrine stimulation loop. We think therefore that imatinib mesylate is less likely to be an effective therapy for Merkel cell carcinoma, unless activating mutations exist in other exons of these receptor kinases.

Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus

“…In addition, we did not detect any mutations in 4 MCC cell lines that contain MCPyV. Consistent with previous studies, we did not find activating muta tions in PDGFRA or KIT (23,(35)(36)(37)(38). We did identify 3 tumors with p53 point substitutions, most notably in 2 specimens with absent expression of MCPyV large T antigen.…”

High KIT and PDGFRA are associated with shorter patients survival in gastroenteropancreatic neuroendocrine tumors, but mutations are a rare event

“…Additionally, we performed mutational analysis in 51 specimens of these rare neoplasms. The fact that we confirmed several expression patterns that have been previously reported using other subgroups of these rare neoplasms supports the validity of our findings (Kartha and Sundram 2008;Micke et al 2004;Rossi et al 2005).…”

“…PDGFRA expression was observed in 33% and was also associated with a higher grading (grade 1 in 15%, grade 2 in 42%, and grade 3 in 50%). Similarly, Kartha and Sundram (2008) found a higher incidence of PDGFRA (87%) in Merkel cell carcinomas, a subtype of poorly differentiated neuroendocrine carcinoma of the skin indicating the higher expression of PDGFRA in poorly differentiated tumors is not a rare molecular event. Furthermore, in our study, a coexpression of high KIT and high PDGFRA was found in 95% (P \ 0.001) of our tumors, and high KIT/ PDGFRA expression was significantly correlated with metastases (P \ 0.001).…”

Co-Expression of KIT Receptor and Its Ligand Stem Cell Factor in Merkel Cell Carcinoma

“…This suggests that the autocrine stimulation of KIT by SCF may represent a major pathway of KIT activation in this tumor. During preparation of this paper, a recent publication reported co-expression of KIT and SCF in 16% of MCC tumors [27]. That rate is substantially lower than the one seen in the present study.…”

“…Differences in positivity rates may result from different antibodies and dilutions, antigen retrieval methods or other variations in staining protocols. Nevertheless, due to the rare co-expression of KIT and SCF in MCC in their report and the SCF staining of surrounding connective tissues, Kartha and Sundram [27] rather favor a paracrine mode for KIT activation. In our study, we have also detected SCF in endothelial and smooth muscle cells as well as in sweat glands, but we found no free SCF in the dermis.…”