Whole Genome Sequencing Illuminates the Genetic and Biological Features Underlying the Transition of SMM to MM

摘要: Abstract 296 A well defined model of disease progression has been established in myeloma based on the transition normal plasma cells to monoclonal gammopathy undetermined significance (MGUS), smouldering (SMM), (MM) and finally cell leukaemia. The most likely mechanism underlying initiation is that primary genetic events, such as IGH translocations or hyperdiploidy confer a proliferative/survival advantage but not truly malignant phenotype. Subsequently, these acquire secondary aberrations are associated with uncontrolled proliferation invasion which manifest bone lesions myelosuppression. We have addressed hypothesis we can gain critical understandings mechanisms leading progression, by defining different events present early pre-clinical stages (SMM) compared those clinical (MM). One essential components acquisition novel hits clonal selection expansion subclone able survive. hypothesise within there substantial heterogeneity at extent this variable, occurring an oligoclonal fashion multiple rather than result linear sequential hits. In study utilized massively parallel sequencing paired from 2 patients who had progressed SMM MM them non-involved DNA. Patients diagnosed SMM, marrow aspirate taken, least 18 months prior being MM. Both samples were taken before patient underwent any treatment. analyzed two time points germline DNA obtain peripheral blood sample, using whole genome identify acquired single nucleotide variants (SNVs), indels samples. Additionally, changes examined along frequency abnormal reads sites. 100 ng genomic CD138 MACsorted white was sequenced 75 bp paired-end GAIIx (Illumina) median depth 32x 98% 1x 84% 20x coverage. Data aligned human (hg19) ELAND v2e SNVs called CASAVA 1.8. both majority found intergenic (range 64–71%) intronic (25–31%) regions. number exons (including UTRs) accounted for only 0.5–1.1% all variants. There no statistical difference distribution between Analysis shows tumour, sample albeit lower levels, indicating dominant clone always transformation SMM. same individual. For example, variant calls be detected incidence 11–15% undetected depth. Acquired almost exclusively (>99%) regions As SNVs, also patient, sample. results presented indicate during process emergence clone, other sub-clones containing non-advantageous passenger mutations selected. Any clones clearly rapidly transform full potential. Therefore, targeted therapeutic approaches aimed may curative, allow propagation minor without mutations. It therefore imperative determine pre-malignant establish course action Disclosures: Humphray: Illumina: Employment. Murray: Ross: Bentley: