Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Olipitz, W.
Defective DNA-mismatch repair in therapy-related myelodysplasia and leukemia
[ Dissertation ] Medical University of Graz; 2001. pp.
- Autor*innen der Med Uni Graz:
- Olipitz Werner
- Betreuer*innen:
- Höfler Gerald
- Sill Heinz
- Altmetrics:
- Abstract:
- Therapy-related myelodyspastic syndrome (t.MDS) and leukemia (t-leuk9 are severe long-term complications following chemo- and radiotherapy as well as stem cell transplantation for a primary malignancy. As only a limited number of cancer patients is affected, it seems obvious to postulate a leukemogenic susceptibility of these individuals. It was intriguing to speculate on the potential role of defective DNA-MMR as a mediator of leukemogenic susceptibility in these patients. We have analyzed a group of 37 patients (7 t-MDS, 26 t-AML, 3 t-CML, 1 t-acute biphenotypic leukaemia). The patients were treated with chemotherapy (n=13), chemo-and radiotherapy (n=17) of radiotherapy (n=7) for various primary malignancies, among which non-Hodkins lymphoma (n013), Hodgkins disease (n=7) and breast cancer (n=4) were the most common. The degree of MSI was assessed using mononucleotide markers BAT25, BAT26, BAT34C4 and dinucleotide markers D2S123, D5S250, D17S250, D13S175, D18S58. Five of 37 (14%) patients displayed high MSI whereas three other patients had low MSI (8%). To address the question of at which stage defective DNA-MMR had developed we analyzed primary tumors of MSI positive patients. As a control group primary tumors form microsatellite stable patients were also screened for MSI. Three of four patients analyzed with high MSI in their t-MDS/t-leuk were also instble in the corresponding primary tumor, whereas none of the primary tumors of low MSI and control group displayed MSI (p=.0182; Fishers exact test). This significant association indicates that these individuals have a propensity to develop MSI suggesting that defective DNA-MMR is most likely of pahtogenetic relevance in the development of their malignancies. To invstigate the biological role of MSI we looked for mutations in exonic repeats of genes known to be targeted by defective DNA-MMR (BAX, TGFbeta RII, IGFII R, Caspase-5, APC, PTEN, E3F4, MBD4, hMSH6, hMSH3) using direct sequencing. However, no mutation was found in any of the high MSI t-MDS/t-leuk and corresponding primary tumor samples. Lack of mutations of repetitive exonic target sequences indicates that there is either no causal involvement of defective DNA-MMR in the pathogenesis of t-MDS/t-leuk or, more likely, there are other yet unidentified target genes related to the pathogenesis of these malignancies. MMR in the pathogenesis of t-MDS/t-leuk or, more likely, there are other yet unidentified target genes related to the pathogenesis of these malignancies.