hMLH1 and hMSH2 gene mutations are present in radial growth-phase cutaneous malignant melanoma cell lines and can be induced further by ultraviolet-B irradiation.
Microsatellite instability and reduced expression of mismatch repair proteins were reported in melanomas. However, little is known about mutational changes of the mismatch repair genes in radial growth-phase melanoma especially following UVB irradiation. To investigate these changes, an in vitro system consisting of radial growth-phase Wistar melanoma cell lines (WM35, WM3211 and WM1650) was established. The cells were UVB irradiated (10 mJ/cm(2)), and evaluated for mutational changes of exon regions 13,16 and 19 (hMLH1) and 6,7 and 12 (hMLH2) of these genes before and after irradiation. The genomic DNAs were PCR amplified and the products were directly sequenced. Transition (C-->T, G-->A, T-->C) and transversion (G-->, A-->T) mutations were found in exons 6,16 and 19. Some were present in both the sham-irradiated and UV-irradiated cells but others were only detected after UVB irradiation. hMLH1 and hMLH2 gene mutations occur early in melanoma tumorigenesis. The ability of UVB irradiation to induce additional mutations in these repair genes suggests its possible role in melanoma pathogenesis. Further investigation will be needed to determine whether mutations such as these contribute to the development of microsatellite instability in melanoma.
Hussein
Mahmoud R
MR
Department of Dermatology, University of Wisconsin, William S Middleton Veteran Hospital, Madison, WI 53705, USA.
Wood
Gary S
GS
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D045744:Cell Line, Tumor; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000235:genetics*; D014466:Ultraviolet Rays
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein