Accumulation of Genetic Alterations and Chromosome Abnormalities in the Onset and Subsequent Progression of Myelodysplastic Syndromes

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This project on the accumulation of genetic events during the onset and the progression of myelodysplastic syndrome (MDS) revealed three major points as follws:(1) Refined mutational events in the Runt domain of the AML1 gone were identified in 5 patients (2.9%) of 176 patients with myeloid leukemia including 85 with MDS. Among these 5 patients, 4 exclusively showed a frame-shift mutation caused by several base-pairs deletion or insertion, resulting in V93del, 1150ins, I168ins and A120ins, respectively. Longitudinal analyses during their disease course revealed all mutations were detected in the first sample, which means AML1 mutations in MDS may be one of the earliest genetic alterations accumulated during the onset and subsequent disease progression.(2) In order to investigate mutational events in DNA repair genes, we tried to optimize sequencing procedures for 1108 exons of 68 genes, and the optimization for 924 exons has already been finished. Among these 68 genes, we analyzed 97 exons of 6 DNA mismatch repair genes using DNA samples from marrow cells from 48 patients with MDS, 48 with malignant lymphoma, and 48 with AML. Among 79 exons (14753 base-pairs in coding regions) successfully analyzed, 31 mutational events were identified, which involved 7 in hMLH1, 1 in hMSH2, 3 in hMSH6, none in hPMS1, and 9 in hPMS2.(3) We validated the usefulness of the International Prognostic Scoring System (IPSS) in our series of de novo MDS patients. We also revealed the prognostic significance of p53 configurations of those patients, and multivariate analysis uncovered its configuration was the most important prognostic factor, followed by the IPSS risk-stratification. Moreover, within the same IPSS category, patients with a p53 mutation showed significantly shorter survival time than those with wild-type configuration