Acquisition of additional mutations drives accelerated progression of NPM1 positive CMML to AML
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ABSTRACT:
PROVIDER: EGAS00001000619 | EGA |
REPOSITORIES: EGA
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We performed exome sequencing on serial samples from a patient with CMML who progressed to AML. The exome sequencing suggests that NPM1, TET2 and DNMT3a mutations were present in the dominant clone in the CMML sample and that NRAS is a new subclonal mutation in the AML sample. Diagnostic data shows the presence of a FLT3-ITD mutation in the AML sample, which is likely to have driven progression. Here we are performing re-sequencing of the putative driver and some passenger mutations which appear to be in the same clone to validate these mutations and to verify the relative quantification of these abnormalities .
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Project description:Genome-wide analysis of single nucleotide polymorphisms in 64 acute myeloid leukemias has revealed that 20% exhibited large regions of homozygosity that could not be accounted for by visible chromosomal abnormalities in the karyotype. Further analysis confirmed that these patterns were due to partial uniparental disomy (UPD). Remission bone marrow was available from five patients showing UPD in their leukemias, and in all cases the homozygosity was found to be restricted to the leukemic clone. Two examples of UPD11p were shown to be of different parental origin as indicated by the methylation pattern of the H19 gene. Furthermore, a previously identified homozygous mutation in the CEBPA gene coincided with a large-scale UPD on chromosome 19. These cryptic chromosomal abnormalities, which seem to be nonrandom, have the characteristics of somatic recombination events and may define an important new subclass of leukemia. Patient No. from Table 1 of Raghavan et al 2005 and Sample name Patient No: 1 = Sample name: AML sample 35 diagnosis Patient No: 1 = Sample name: AML sample 107 remission Patient No: 2 = Sample name: AML sample 37 diagnosis Patient No: 3 = Sample name: AML sample 10 diagnosis Patient No: 3 = Sample name: AML sample 44 remission Patient No: 4 = Sample name: AML sample 20 diagnosis Patient No: 5 = Sample name: AML sample 65 diagnosis Patient No: 6 = Sample name: AML sample 69 diagnosis Patient No: 6 = Sample name: AML sample 94 remission Patient No: 7 = Sample name: AML sample 40 diagnosis Patient No: 7 = Sample name: AML sample 41 remission Patient No: 8 = Sample name: AML sample 64 diagnosis Patient No: 9 = Sample name: AML sample 7 diagnosis Patient No: 10 = Sample name: AML sample 49 diagnosis Patient No: 10 = Sample name: AML sample 106 remission Patient No: 11 = Sample name: AML sample 76 diagnosis Patient No: 12 = Sample name: AML sample 79 diagnosis Keywords: DNA copy number, loss of heterozygosity
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