Subject(s)
Hand Dermatoses/pathology , Keratoderma, Palmoplantar/pathology , Fingers , Humans , Male , Middle AgedSubject(s)
Buttocks , Keratosis/diagnosis , Porokeratosis/diagnosis , Pruritus/diagnosis , Aged , Biopsy , Curettage , Female , Humans , Keratosis/pathology , Mineral Oil/therapeutic use , Myristates/therapeutic use , Porokeratosis/pathology , Porokeratosis/therapy , Pruritus/pathology , Skin/pathology , Treatment OutcomeABSTRACT
AIMS: Elevated expression of DNA repair and replication genes has been reported in thick, non-fixed primary melanomas that subsequently went on to metastasize, when compared to non-recurrent primary tumours. This increased expression could contribute to the extreme resistance shown by melanoma to DNA-damaging chemotherapeutics. We have investigated the hypothesis that levels of key DNA repair and replication proteins are prognostic biomarkers in melanoma. METHODS AND RESULTS: We used a tissue microarray containing samples from all stages of melanomagenesis to investigate the hypothesis that levels of key DNA repair and replication proteins are prognostic biomarkers in a larger, more representative and readily available set of fixed primary melanomas. High expression of topoisomerase IIα (TOP2A), that relieves torsional stress during DNA replication, and XRCC5 (Ku80), required for DNA double-strand break repair, were associated with significantly worse survival. CONCLUSIONS: Two (XRCC5 and TOP2A) of seven DNA repair and replication proteins studied were prognostic for melanoma.
Subject(s)
Antigens, Neoplasm/metabolism , DNA Helicases/metabolism , DNA Repair , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins/metabolism , Melanoma/secondary , Skin Neoplasms/pathology , Biomarkers, Tumor/metabolism , Disease Progression , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Ku Autoantigen , Lymph Nodes/pathology , Male , Melanoma/genetics , Melanoma/metabolism , Melanoma/mortality , Poly-ADP-Ribose Binding Proteins , Prognosis , Proportional Hazards Models , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Skin Neoplasms/mortality , Survival Rate , Tissue Array Analysis , United Kingdom/epidemiologyABSTRACT
AIMS: Galectin-3 plays an important role in adhesion, proliferation, differentiation, angiogenesis and metastasis in multiple tumours. To investigate the role of galectin-3 in melanoma pathogenesis we examined the expression of galectin-3 in melanocytic lesions and analysed the correlation between galectin-3 expression and clinicopathologic factors including patient survival and BRAF mutation status. METHODS: We evaluated the expression of galectin-3 in 53 cases of benign naevi, 31 cases of dysplastic naevi, 59 in-situ melanomas, 314 cases of primary melanoma and 69 metastatic melanomas using tissue microarray and immunohistochemistry. RESULTS: Marked differences in expression of galectin-3 were seen between different categories of melanocytic lesions (ANOVA p<0.0001). An increase in expression of galectin-3 between benign naevi and thin primary melanomas and a progressive decrease in expression between thin primary melanomas and thicker melanomas or metastatic melanomas was seen. Strong galectin-3 expression was associated with improved overall survival (p=0.002 and p=0.0002 for cytoplasmic and nuclear expression, respectively) and melanoma-specific survival (p=0.017 and p=0.003 for cytoplasmic and nuclear expression, respectively). A multifactorial Cox regression analysis suggested that galectin-3 expression was an independent prognostic marker for overall survival in melanoma (risk ratio 0.73, 95% CI 0.547-0.970, p=0.031 for cytoplasmic expression and risk ratio 0.76, 95% CI 0.587-0.985, p=0.036 for nuclear expression). No association between galectin-3 expression and BRAF mutation status was observed. CONCLUSION: This study suggests that galectin-3 is a marker of progression in melanocytic lesions and a novel prognostic marker in primary melanoma.
Subject(s)
Galectin 3/metabolism , Melanoma/metabolism , Melanoma/pathology , Neoplasm Proteins/metabolism , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Adult , Aged , Analysis of Variance , DNA Mutational Analysis , Disease Progression , Female , Humans , Immunohistochemistry , Male , Melanoma/genetics , Microarray Analysis , Middle Aged , Mutation , Prognosis , Proportional Hazards Models , Proto-Oncogene Proteins B-raf/genetics , Risk Factors , Scotland , Skin Neoplasms/genetics , Survival AnalysisABSTRACT
The incidence of cutaneous melanoma is rising rapidly in a number of countries. The key environmental risk factor is exposure to the ultraviolet (UV) component in sunlight. The nucleotide excision repair (NER) pathway deals with the main forms of UV-induced DNA damage. We have investigated the hypothesis that polymorphisms in NER genes constitute genetic susceptibility factors for melanoma. However, not all melanomas arise on sun-exposed sites and so we investigated the hypothesis that genes involved in other pathways for the repair of oxidative DNA damage may also be involved in susceptibility to melanoma. Scotland, with its high incidence of melanoma and stable homogeneous population, was ideal for this case-control study, involving 596 Scottish melanoma patients and 441 population-based controls. Significant associations were found for the NER genes ERCC1 and XPF, with the strongest associations for melanoma cases aged 50 and under [ERCC1 odds ratio (OR) 1.59, P = 0.008; XPF OR 1.69, P = 0.003]. Although an XPD haplotype was associated with melanoma, it did not contain the variant 751 Gln allele, which has been associated with melanoma in some previous studies. No associations were found for the base excision repair and DNA damage response genes investigated. An association was also found for a polymorphism in the promoter of the vitamin D receptor gene, VDR (OR 1.88, P = 0.005). The products of the two NER genes, ERCC1 and XPF, where associations with melanoma were found, act together in a rate-limiting step in the repair pathway.
