Ki-67, Bcl-2 and p53 expression in primary and metastatic melanoma

Abstract

The aim of this study was to clarify the roles of the tumour proliferation marker Ki-67, the anti-apoptotic protein Bcl-2 and the cell cycle regulator p53 in primary cutaneous and metastatic melanoma. One hundred and seventeen primary melanomas and 18 metastatic tissue samples were analysed for immunohistochemical expression of Ki-67, Bcl-2 and p53. The staining results were correlated with disease progression and clinical outcome. The patient population comprised patients diagnosed with melanoma between 1988 and 1991. The clinical follow-up period for disease recurrence was 4.6 years (median; range, 0.2-7.5 years) and the follow-up period for overall survival was 10.0 years (median; range, 8.6-15.6 years). Ki-67 expression was not a prognostic factor in primary melanoma. High Bcl-2 expression was associated with such adverse prognostic factors as male gender, old age of the patient and tumour ulceration. High Bcl-2 expression was also associated with an adverse prognosis in intermediate-thickness (1.01-4.0 mm) melanomas (n=52) for disease-free (P=0.09) and overall (P=0.08) survival. In multivariate analysis, tumour thickness was the strongest prognostic factor for disease-free survival (P<0.01). High p53 expression indicated a poorer prognosis (P=0.05). In metastatic melanoma, the expression levels of Bcl-2 and p53 were lower than those in their primary counterparts (P=0.08 for each). Ki-67 expression showed no remarkable changes. It can be concluded that high p53 expression in tumour cells is associated with a poorer prognosis in primary melanoma, and high Bcl-2 expression in tumour cells is an adverse prognostic marker in intermediate-thickness primary melanoma.

Melanoma: from mutations to medicine

“…Its expression has been seen to be up-regulated by a variety of growth factors, including KIT ligand (SCF) (Zhai et al 1996;von Willebrand et al 2005), NRAS (Borner et al 1999), andMITF (McGill et al 2002). BCL2 expression has been correlated with several poor prognostic features that include presence of ulceration and patient survival (Leiter et al 2000;Ilmonen et al 2005). Genetic deletion of BCL2 in the mouse germline results in a striking hair-graying phenotype that was found to result from abrupt death of hair follicle melanocyte stem cells at approximately postnatal day 8 (Nishimura et al 2005).…”

Malignant melanoma: genetics and therapeutics in the genomic era

“…Expression of activated NRAS in melanoma cell lines can also up-regulate Bcl-2 (Borner et al 1999). Both normal melanocytes and melanoma cells express Bcl-2 (Plettenberg et al 1995), and several studies have correlated elevated Bcl-2 with adverse clinical and pathological factors such as tumor ulceration and patient survival, particularly in thicker primary melanomas (Leiter et al 2000;Ilmonen et al 2005). Moreover, germline knockout of Bcl-2 results in death of melanocyte stem cells within the hair follicle at a discrete developmental state (Nishimura et al 2005), demonstrating a critical role for Bcl-2 in the melanocyte lineage.…”

Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma

“…3 Although linked to exposure to ultraviolet light, it is widely accepted that both genotypic and phenotypic changes in melanocytes predispose to melanocyte transformation and the onset of melanoma. 4,5 Surprisingly, p53 mutations are very rare in melanoma, but activity is, however, impaired through direct or indirect inactivation of key elements of this pathway, including through the suppression of APAF-1 expression, 6 loss of PTEN function, 7 dysregulation of Bcl-2 expression, 8 upregulation of the anti-apoptotic protein Mcl-1 together with its altered slice variant expression 9,10 and the ER chaperone GRP78. [11][12][13] Oncogenic mutations, however, in the Ras/Raf pathway are the most well-described genetic mutations associated with melanoma development and progression.…”