Methylation of tumour suppressor gene promoters in the presence and absence of transcriptional silencing in high hyperdiploid acute lymphoblastic leukaemia

Authors

  • Kajsa Paulsson,

    1. Cancer Research UK Medical Oncology Centre, Barts and the London School of Medicine, Queen Mary College, London
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      Present address: Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.

  • Qian An,

    1. Cancer Genomics Group, Cancer Sciences Division, University of Southampton, Southampton
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    • Previous address: Leukaemia Research Cytogenetics Group, Cancer Sciences Division, University of Southampton, UK.

  • Anthony V. Moorman,

    1. Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, University of Newcastle, Newcastle Upon Tyne
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    • Previous address: Leukaemia Research Cytogenetics Group, Cancer Sciences Division, University of Southampton, UK.

  • Helen Parker,

    1. Cancer Genomics Group, Cancer Sciences Division, University of Southampton, Southampton
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    • Previous address: Leukaemia Research Cytogenetics Group, Cancer Sciences Division, University of Southampton, UK.

  • Gael Molloy,

    1. Cancer Research UK Medical Oncology Centre, Barts and the London School of Medicine, Queen Mary College, London
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  • Teresa Davies,

    1. Bristol Genetics Laboratory, Southmead Hospital, Westbury-on-Trym, Bristol
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  • Mike Griffiths,

    1. West Midlands Regional Genetics Laboratory, Birmingham Women’s Hospital, Birmingham
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  • Fiona M. Ross,

    1. Wessex Regional Genetic Laboratory, Salisbury District Hospital, Salisbury, UK
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  • Julie Irving,

    1. Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, University of Newcastle, Newcastle Upon Tyne
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  • Christine J. Harrison,

    1. Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, University of Newcastle, Newcastle Upon Tyne
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    • Previous address: Leukaemia Research Cytogenetics Group, Cancer Sciences Division, University of Southampton, UK.

  • Bryan D. Young,

    1. Cancer Research UK Medical Oncology Centre, Barts and the London School of Medicine, Queen Mary College, London
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  • Jon C. Strefford

    1. Cancer Genomics Group, Cancer Sciences Division, University of Southampton, Southampton
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    • Previous address: Leukaemia Research Cytogenetics Group, Cancer Sciences Division, University of Southampton, UK.


Dr Kajsa Paulsson, Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden. E-mail: kajsa.paulsson@med.lu.se

Summary

Promoter methylation is a common phenomenon in tumours, including haematological malignancies. In the present study, we investigated 36 cases of high hyperdiploid (>50 chromosomes) acute lymphoblastic leukaemia (ALL) with methylation-specific multiplex ligase-dependent probe amplification to determine the extent of aberrant methylation in this subgroup. The analysis, which comprised the promoters of 35 known tumour suppressor genes, showed that 16 genes displayed abnormal methylation in at least one case each. The highest number of methylated gene promoters seen in a single case was thirteen, with all but one case displaying methylation for at least one gene. The most common targets were ESR1 (29/36 cases; 81%), CADM1 (IGSF4, TSLC1; 25/36 cases; 69%), FHIT (24/36 cases; 67%) and RARB (22/36 cases; 61%). Interestingly, quantitative reverse transcription-polymerase chain reaction showed that although methylation of the CADM1 and RARB promoters resulted in the expected pattern of downregulation of the respective genes, no difference could be detected in FHIT expression between methylation-positive and -negative cases. Furthermore, TIMP3 was not expressed regardless of methylation status, showing that aberrant methylation does not always lead to gene expression changes. Taken together, our findings suggest that aberrant methylation of tumour suppressor gene promoters is a common phenomenon in high hyperdiploid ALL.

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