Expression of rasGTPase activating protein in basal cell carcinoma of the skin.

The ras proto-oncogene, a key component in the signal transduction cascade of activated growth factors, is involved in multiple tumor types, including basal cell carcinoma (BCC). rasGTPase activating protein (rasGAP), is a dual function protein in the ras signaling pathway, i.e., it downregulates activated ras via its catalytic domain, and it also participates in the downstream effector signaling pathway by mediating protein-protein interaction. Missense mutations presumably leading to rasGAP activation were previously detected in this gene, in a subset of BCCs. To assess the role of rasP21 and rasGAP in BCC tumorigenesis, we performed an immunohistochemical analysis of 48 BCCs, of which 45 were of the circumscribed variant (indolent-growth tumors) and the remaining 3 (2 morpheaform, 1 infiltrative), were aggressive-growth variants. rasGAP overexpression was demonstrated in 7 of 48 BCC cases, i.e., in 4 (8.8%) of 45 indolent-growth cases and in all of the 3 aggressive-growth cases. We detected tumor-specific reduction of rasP21 levels in 5 (11.1%) of 45 cases. There was no overlap between the tumors displaying rasGAP and rasP21 alternations and a high proliferation index, as assessed by Ki-67 staining, except for one case of aggressive-growth variant. We conclude that rasGAP overexpression is associated with BCC tumorigenesis in a ras-independent manner, is not reflective of the proliferation status of the tumor, and is more characteristic of aggressive-growth BCCs.