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NOVEL METHYLATION-DEPENDENT MARKERS/TUMOR SUPPRESSOR GENES INVOLVED IN THE DEVELOPMENT OF RENAL CELL CANCERстатья
- Авторы: Zabarovsky E.R., Braga E.A., Loginov V.I., Senchenko V.N., Kudryavtseva A.V., Dmitriev A.A., Khodyrev D.S., Pavlova T., Rynditch A.V., Lerman M.I., Kashuba V.I.
- Сборник: HORIZONS IN CANCER RESEARCH
- Том: 42
- Глава в коллективной монографии
- Год издания: 2011
- Издательство: Nova Science Publishers
- Местоположение издательства: Hauppauge, NY, United States
- Первая страница: 129
- Последняя страница: 152
- Номер статьи: 5
- Аннотация: In this article we present our data from the loss of heterozygosity (LOH). real-time quantitative PCR genomic mapping and expression studies till identification of genes biomarkers that could be used for diagnosis and even gene therapy of clear cell renal cancer (RCC).Recently we have developed and used Notl microarrays (NMA) for our experiments. Creation of microarrays on the genomic level would be very important as it may give information unavailable on the mRNA/cDNA level. NMA gives the opportunity to detect simultaneously and differentially copy number and methylation changes. Thus they allow us to check cancer cells for genetic and epigenetic abnormalities. These NMA can be used for individuals, normal tumor pairs, different cell types, etc. At present, we analyzed over 100 RCC samples. In the study more than 190 genes from human chromosome 3 were analyzed. Many genes were found to be methylated in a very high fraction of cancer samples (more than 80%). These genes can be divided into two classes: RCC specific and common for several types of cancer. Some examples of genes involved in several cancers: ЫШТ24 (AF135524). BHLHB2. LOC285205, NBEAL2 (KIAA0540), FLJ44898 (AK126846), GATA-2. RARbetal. RBSP3 (CTDSPL). \HL. Many methylated genes were unknown previously to be involved in the development of RCC. Methylation of 16 genes was confirmed by methyl-specific PC'R and bisulfite sequencing. Methylation status of the genes correlated with expression (15 genes were tested). Four genes were tested functionally and demonstrated growth inhibiting activity proving that NMA are efficient instruments to discover cancer causing genes and especially tumor suppressor genes. We foimd that several tumor suppressor genes in the AP20 and LUCA 3p21.3 regions were со-regulated in tumors.It is interesting that for two genes—RASSFIA and RBSP3—we foimd an exceptionally high incidence of single-base mutations Altogether in 144 sequenced RASSFIA clones (exons 1-2), 129 mutations were detected (mutation frequency. MF=0.23 per lOObp) and in 98 clones of exons 3-5 we foimd 146 mutations (MF=0.29). In 85 sequenced RBSP3 clones, 89 mutations were foimd (MF=0.10). The mutations appeared de noxo during cell proliferation. They diminished the ability of corresponding transgenes to suppress cell and tumor growth implying a loss of function. These high levels of somatic mutations were foimd both in cancer biopsies and cancer cell lines. This is the first report of high frequencies of somatic mutations in RASSF1 and RBSP3 in RCC suggesting it may underlay the mutator phenotype of cancer. Somatic hypermutations in tumor suppressor genes involved in major human malignancies offer a novel insight in cancer development, progression and spread.Our results suggested the following promising 3p genes, biomarkers for early detection, diagnosis and prognosis of kidnev cancer, namely. RASSFIA, RAR-beta2, SEMA3B, USP4, GPX1, RHOA, RBSP3, HYAL1, SEMA3B, NPRL2, ACY1, CHL1, BCL6, ETV5, GPR149, 2HJDT16P. SOX2, LOC44094S, GATA-2, NBEAL2 and ZNF659.
- Добавил в систему: Логинов Виталий Игоревич