title: Defective DNA-mismatch repair: a potential mediator of leukemogenic susceptibility in therapy-related myelodysplasia and leukemia.
abstract: We investigated the potential role of defective DNA-mismatch repair (MMR) as a mediator of leukemogenic susceptibility in patients with therapy-related myelodysplasia (t-MDS) and leukemia (t-leuk). Thirty-seven individuals with t-MDS/t-leuk were analyzed for microsatellite instability (MSI), the hallmark of defective DNA-MMR. Using standardized international criteria, 5/37 (14%) patients displayed high MSI, whereas 3 other patients had low MSI (8%). To determine the stage at which MSI had developed, we analyzed the primary tumors of 12 patients. Three of 4 patients with high MSI t-MDS/t-leuk also had microsatellite unstable primary tumors. Conversely, MSI was not detected in any primary malignancy of patients with low MSI or microsatellite stable t-MDS/t-leuk (P = 0.0182). In the high MSI group, we further investigated genes targeted by defective DNA-MMR (BAX, TGFBRII, IGFIIR, Caspase-5, APC, PTEN, E2F4, MBD4, MSH6, and MSH3) in both primary tumor and t-MDS/t-leuk. However, no mutation was found in any gene. The significant association of MSI in t-MDS/t-leuk and corresponding primary tumors suggests that defective DNA-MMR confers leukemogenic susceptibility to this cohort of patients.
authors.affiliation: Division of Hematology, Department of Medicine, Karl-Franzens University, Graz, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Olipitz
authors.forename: Georg
authors.initials: G
authors.lastname: Hopfinger
authors.forename: Ricardo C T
authors.initials: RC
authors.lastname: Aguiar
authors.forename: Eberhard
authors.initials: E
authors.lastname: Gunsilius
authors.forename: Michael
authors.initials: M
authors.lastname: Girschikofsky
authors.forename: Claudia
authors.initials: C
authors.lastname: Bodner
authors.forename: Karin
authors.initials: K
authors.lastname: Hiden
authors.forename: Werner
authors.initials: W
authors.lastname: Linkesch
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.forename: Heinz
authors.initials: H
authors.lastname: Sill
mesh_terms: D000328:Adult; D000368:Aged; D020137:Base Pair Mismatch / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004260:DNA Repair / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000139:chemically induced* / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics