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Prognostic Significance of Nuclear ING3 Expression in Human Cutaneous Melanoma

Authors' Affiliations: Departments of ¹ Dermatology and Skin Science and ² Pathology, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada

Requests for reprints: Gang Li, Jack Bell Research Centre, 2660 Oak Street, Vancouver, BC, Canada V6H 3Z6. Phone: 604-875-5826; Fax: 604-875-4497; E-mail: gangli{at}interchange.ubc.ca.

Purpose: The novel tumor-suppressor ING3 has been shown to modulate transcription, cell cycle control, and apoptosis. Our previous study showed that ING3 promotes UV-induced apoptosis via the Fas/caspase-8–dependent pathway in melanoma cells. To investigate the putative role of ING3 in the development of melanoma, we examined the expression of ING3 in melanocytic lesions at different stages and analyzed the correlation between ING3 expression and clinicopathologic variables and patient survival.

Experimental Design: Using tissue microarray and immunohistochemistry, we evaluated nuclear and cytoplasmic ING3 staining in 58 dysplastic nevi, 114 primary melanomas, and 50 metastatic melanomas.

Results: Nuclear ING3 expression was remarkably reduced in malignant melanomas compared with dysplastic nevi (P < 0.001), which was significantly correlated with the increased ING3 level in cytoplasm (P < 0.05). Furthermore, the reduced nuclear ING3 expression was significantly correlated with a poorer disease-specific 5-year survival of patients with primary melanoma, especially for the high-risk melanomas (thickness 2.0 mm) with the survival rate reducing from 93% for patients with strong nuclear ING3 staining in their tumor biopsies to 44% for those with negative-to-moderate nuclear ING3 staining (P = 0.004). Strikingly, our multivariate Cox regression analysis revealed that reduced nuclear ING3 expression is an independent prognostic factor to predict patient outcome in primary melanomas (P = 0.038).

Conclusions: Our data indicate that ING3 may be an important marker for human melanoma progression and prognosis as well as a potential therapeutic target.

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