Genetic profiling of haematological malignancies

Abstract

Acute lymphoblastic leukaemia (ALL) accounts for approximately 3% of all cancers, and leads to more than 4250 deaths a year. The different classes of leukaemia comprise numerous heterogeneous subgroups, which differ in their cellular and molecular characteristics, as well as their response to therapy. Accurate risk stratification is essential for tailoring of therapy, and achieving optimal outcome in contemporary treatment regimes. Based upon clinical features and cytogenetic and molecular diagnostics, the majority of ALL patients are assigned to one of the following prognostically significant subtypes having; ETV6-RUNX1, BCR-ABL1 or TCF3-PBX1 fusions, MLL rearrangements, high hyperdiploidy (HeH) with >50 chromosomes, hypodiploidy or T-ALL. Whilst in leukaemogenesis, and provide diagnostic and prognostic markers, co-operating oncogenic aberrations are often required for the production of a full leukaemic phenotype. A number of additional aberrations have been identified within some cytogenetic subgroups, but the full complement of cooperating abnormalities, and their distribution within ALL subtypes remains to be defined. these genetic abnormalities are important In this study the genomic changes in a total of 94 ALL patients from the ETV6-RUNX1 (n=34), iAMP21 (n=19) and unclassified (n=41) patient subgroups were characterised using cytogenetics, FISH, array comparative genomic hybridisation, molecular copy number counting, mutation analysis, qRT-PCR and targeted gene expression arrays. This approach allowed the identification of a range of large scale and submicroscopic aberrations, targeting multiple known and novel regions, including a number of genes. The elucidation of pathways and genes dysregulated in these malignant subgroups has provided further insight into the underlying cause of the disease phenotype. The PDE9A and TBL1XR1 genes were implicated in the pathogenesis of iAMP21 and ETV6-RUNX1 patients, respectively. Additionally, the potential prognostic significance of the ADD3 gene in ETV6-RUNX1 positive ALL was revealed.

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