hrvatski

Uloga postreplikacijskog MMR popravka u tumorigenezi

Impaired cellular DNA mismatchrepair (MMR) mechanisms are involved in cancer initiation and progression. Cancer cells are thought to have a mutator phenotype in which an elevated rate of mutation persists. The defective functioning of MMR proteins will consequently give rise to microsatellite instability (MSI). The importance of MSI phenotype in human tumors is an emerging field demonstrating its involvement in the clinical course of the disease, response to therapy, and survival outcomes (Clark et al 2013, Hause et al, 2016). The MMR system, which consists of a group of proteins specialized in recognizing mispaired bases and small loops of insertion or deletion, checks the post-replicated DNA strand. MMR machinery is coded by 8 genes in the human: hMLH1 (3p21), hPMS1 (hMLH2) (2q31.1), hMLH3 (14q24.3), hPMS2 (hMLH4) (7q22.2), hMSH2 (2p21), hMSH3 (5q14.1), hMSH5 (6p21.3), hMSH6 (2p16) (Fishel 2015 ; Loeb, 2016 ; Modrich 2016). Variations and alterations in DNA repair genes are important factors for specific tumor susceptibility. In a group of 50 intracranial meningiomas, we investigated the involvement of two major MMR genes, MLH1 and MSH2, using microsatellite markers D1S1611 and BAT26 amplified by polymerase chain reaction and visualized by gel electrophoresis on high- resolution gels. Furthermore, genes DVL3 (D3S1262), AXIN1 (D16S3399), and CDH1 (D16S752) were also investigated for microsatellite instability (Pećina-Šlaus et al, 2017a). Our study revealed constant presence of microsatellite instability in meningioma patients when compared to their autologous blood DNA (Pećina-Šlaus et al, 2016a). Altogether 38% of meningiomas showed microsatellite instability at one microsatellite locus, 16% on two, and 13.3% on three loci. The percent of detected microsatellite instability for MSH2 gene was 14%, and for MLH1, it was 26%, for DVL3 22.9%, for AXIN1 17.8%, and for CDH1 8.3%. Since markers also allowed for the detection of loss of heterozygosity, gross deletions of MLH1 gene were found in 24% of meningiomas. Genetic changes between MLH1 and MSH2 were significantly positively correlated (p=0.032). We also noted a positive correlation between genetic changes of MSH2 and DVL3 genes (p=0.034). No significant associations were observed when MLH1 or MSH2 was tested against specific histopathological meningioma subtype or World Health Organization grade. However, genetic changes in DVL3 were strongly associated with anaplastic histology of meningioma (χ2=9.14 ; p=0.01). We believe that our study contributes to a better understanding of the genetic profile of human intracranial meningiomas and suggests that meningiomas harbor defective cellular DNA MMR mechanisms (Pećina- Šlaus et al, 2016b ; Pećina-Šlaus et al, 2017b). Loss of proper functioning of DNA damage repair genes and proteins, whether through mutations or loss of their expression, is strongly correlated to the introduction of genomic instability and consequent tumorigenesis.

meningioma ; microsatellite instability ; loss of heterozygosity ; MLH1 MSH2 ; BAT26 ; D3S1611 ; AXIN1 ; CDH1 ; DVL3

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