Abstract
The cyclin-dependent kinase inhibitor p27 plays important roles in cell proliferation, cell motility, and apoptosis. Interestingly, the nuclear and cytoplasmic p27 exert opposite biological functions. In this study, we investigated the prognostic impact of subcellular p27 expression. We constructed melanoma tissue microarrays in a large series of melanoma patients, including 29 normal nevi, 52 dysplastic nevi, 270 primary melanomas, and 148 metastatic melanomas. The expression level of subcellular p27 in different stages of melanocytic lesions and its prognostic significance were evaluated. Compared with dysplastic nevi, nuclear p27 expression was remarkably reduced in primary melanomas and further reduced in metastatic melanoma (P < 0.001 for both), whereas cytoplasmic p27 expression is significantly increased from dysplastic nevi to primary melanomas (P = 0.032) and further increased in melanoma metastases (P = 0.037). Although loss of nuclear p27 expression is correlated with a worse 5-year survival of primary melanoma patients in Kaplan-Meier analysis (P = 0.046), it is not a prognostic factor by multivariate Cox regression analysis. On the contrary, Kaplan-Meier analysis showed that gain of cytoplasmic p27 was associated with a poor 5-year survival of metastatic melanoma patients (P < 0.001). Multivariate Cox regression analysis revealed that positive cytoplasmic p27 expression is an independent prognostic factor to predict metastatic melanoma patient outcome. Cytoplasmic p27 may serve as a promising prognostic marker for metastatic melanoma. Because there is no reliable prognostic marker for metastatic melanoma, our finding may have important clinical implications using cytoplasmic p27 as a prognostic biomarker for advanced melanoma.
Highlights
Human cutaneous malignant melanoma is an aggressive type of skin cancer, and its incidence in individuals of European origin continues to rise worldwide [1]
In all 418 melanoma patients, we found that positive nuclear p27 expression significantly decreased from 51% in early stage (AJCC I and II) to 25% in advanced stage (AJCC III and IV; P < 0.001, c2 test), whereas positive cytoplasmic p27 expression significantly increased from 41% in early stage to 51% in advanced stage (P 1⁄4 0.037, c2 test, Table 1)
Our results clearly indicated that similar to American Joint Committee on Cancer (AJCC) stages, which have been widely accepted as independent prognostic factors for melanoma patient survival, cytoplasmic p27 expression is an independent prognostic factor for both overall (HR 1⁄4 1.88; 95% confidence intervals (CIs), 1.36–2.61; P < 0.001) and disease-specific 5-year survival (HR 1⁄4 1.91; 95% CI, 1.31–2.69; P < 0.001; Table 3)
Summary
Human cutaneous malignant melanoma is an aggressive type of skin cancer, and its incidence in individuals of European origin continues to rise worldwide [1]. Melanoma accounts for only 4% of all dermatologic cancers, it is responsible for more than 80% of deaths from skin cancers, and the 10-year survival. Authors' Affiliations: 1Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia and 2Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada. Rate for patients with metastatic melanoma is less than 10% [3, 4]. Identifying biomarkers in conjunction with traditional cancer staging and prognosis could improve early diagnosis and patient care [5]. Despite the efforts that have been made, reliable biomarkers, especially for metastatic melanomas, are still lacking. We investigated the prognostic impact of subcellular p27 expression
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