1. Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia
- Author
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Parker, H., Rose-Zerilli, M. J. J., Larrayoz, M., Clifford, R., Edelmann, J., Blakemore, S., Gibson, J., Wang, J., Ljungström, Viktor, Wojdacz, T. K., Chaplin, T., Roghanian, A., Davis, Z., Parker, A., Tausch, E., Ntoufa, S., Ramos, S., Robbe, P., Alsolami, R., Steele, A. J., Packham, G., Rodriguez-Vicente, A. E., Brown, L., McNicholl, F., Forconi, F., Pettitt, A., Hillmen, P., Dyer, M., Cragg, M. S., Chelala, C., Oakes, C. C., Rosenquist, Richard, Stamatopoulos, K., Stilgenbauer, S., Knight, S., Schuh, A., Oscier, D. G., Strefford, J. C., Parker, H., Rose-Zerilli, M. J. J., Larrayoz, M., Clifford, R., Edelmann, J., Blakemore, S., Gibson, J., Wang, J., Ljungström, Viktor, Wojdacz, T. K., Chaplin, T., Roghanian, A., Davis, Z., Parker, A., Tausch, E., Ntoufa, S., Ramos, S., Robbe, P., Alsolami, R., Steele, A. J., Packham, G., Rodriguez-Vicente, A. E., Brown, L., McNicholl, F., Forconi, F., Pettitt, A., Hillmen, P., Dyer, M., Cragg, M. S., Chelala, C., Oakes, C. C., Rosenquist, Richard, Stamatopoulos, K., Stilgenbauer, S., Knight, S., Schuh, A., Oscier, D. G., and Strefford, J. C.
- Abstract
Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis. With next-generation sequencing we detected mutations of SETD2 in an additional 3.8% of patients (23/602). In most cases, SETD2 deletions or mutations were often observed as a clonal event and always as a mono-allelic lesion, leading to reduced mRNA expression in SETD2-disrupted cases. Patients with SETD2 abnormalities and wild-type TP53 and ATM from five clinical trials employing chemotherapy or chemo-immunotherapy had reduced progression-free and overall survival compared with cases wild type for all three genes. Consistent with its postulated role as a tumour suppressor, our data highlight SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease., De tre första författarna delar förstaförfattarskapet.
- Published
- 2016
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