[Point somatic mutations in bladder cancer: key carcinogenesis events, diagnostic markers and therapeutic targets]

Abstract

Development of bladder cancer (BC) involves accumulating several genetic alterations in somatic cells: point mutations, extended deletions in the localization of tumor suppressor genes, amplification of oncogenes, aberrant DNA methylation, changes in the expression pattern of regulatory RNAs and numerous structural genes. From all of the above, point mutations have the greatest potential as diagnostic markers, as they frequently occur in carcinogenesis, characterize initiation and further clonal evolution of malignancy and represent a change in DNA detectable by routine molecular genetic methods. If we look at the clinical classification of bladder cancer, 90% of the BC presented by urothelial carcinoma, 80% of patients had superficial and 20% - of muscle-invasive tumors. The differences in morphological classification, staging and prognosis of bladder cancer represent different pathogenic pathways of tumor development. Superficial bladder cancer develops through a stage of hyperplasia involving activation of mutations in the genes FGFR3, PIK3CA, HRAS, ERBB2, TERT and others. It is shown that frequent point mutations FGFR3, PIK3CA and TERT are present in the tumor cells in the urine sediment and can be considered as markers for non-invasive molecular genetic diagnosis of primary BC and for monitoring of disease recurrence. Muscle-invasive bladder cancer develops through the stages of dysplasia and carcinoma in situ, in which mutations initially occur in key suppressor genes (TP53 and RB1) and a number of chromatin remodeling genes. This leads to genomic instability and multiple chromosome aberrations that are subjected to selection in the further clonal evolution of tumors towards predominance of more malignant subclones. This review presents systematized information about the main mutations in BC carcinogenesis, their role in the primary tumor progression, metastasizing and role as a target for diagnosis and targeted therapy.

Keywords: bladder cancer; genetic marker; somatic mutation.