Melanoma Prognostic and Risk Factors. Summary of the Doctoral Thesis

Abstract

Cutaneous malignant melanoma (CMM) is a skin cancer that develops through the interaction of environmental factors, pigmentation phenotype and genotype. CMM incidence and mortality rates are increasing worldwide. The prognosis of CMM is mainly determined by the patient’s clinical characteristics and the histological parameters of the tumor. The risk of developing melanoma is associated with mutations in genes CDKN2A and CDK4 and also MC1R gene polymorphisms. The aim of the study was to evaluate the epidemiology, clinical and histopathological features of CMM in relation to the prognosis of the disease and to assess genetic risk factors for melanoma in Latvian population. A retrospective study of a database of 984 CMM patients treated at the Riga Eastern Clinical University Hospital Latvian Oncology Center (RAKUS LOC) between 1998 and 2008 was conducted. The genetic analysis included 228 melanoma patients. Gene CDKN2A was analysed in CMM patients with a family history of recurrent melanoma, pancreatic and cerebral cancer, young CMM patients (<40 y) and patients with multiple primary melanomas. Also, analysis of exon 2 of gene CDK4 was carried out. To evaluate the impact of gene MC1R polymorphisms on the risk of melanoma gene MC1R was sequenced in 200 melanoma patients and 200 control subjects. The study showed a significant increase of melanoma incidence in RAKUS LOC during the time between 1998 and 2008 (coefficent=0.56; 95%CI=0.15-1.05; p=9.67x10^-3). Nodular CMM (39.2%) was the most common tumor type. Ulceration was present in 45.2% of cases. A significant decrease in the mean Breslow thickness of the tumors was observed (coefficient = -0.37, 95%CI= -0.60 to -0.15, p=0.005) over the study period; however, mean tumor thickness remained high and was 6.0 mm. The first mutation in the gene CDKN2A among Latvian melanoma patients, i.e. 5 bp deletion in the CDKN2A/p14^ARF promoter region (c.-20676_- 20682delGTACG), was detected. Analysis of gene CDK4 revealed a second and third Latvian melanoma patient with the mutation R24H. Twenty six different MC1R gene polymorphisms were identified, four of which - Val60Leu, Val92Met, Arg151Cys and Arg160Try were associated with a higher melanoma risk, the increase being 2-4 times. Furthermore, the risk was higher in persons with dark hair and skin type III / IV.