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Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease

Lin, Thet Thet; Norris, Kevin; Heppel, Nicole H.; Pratt, Guy; Allan, James M.; Allsup, David J.; Bailey, James; Cawkwell, Lynn; Hills, Robert; Grimstead, Julia W.; Jones, Rhiannon E.; Britt-Compton, Bethan; Fegan, Chris; Baird, Duncan M.; Pepper, Chris

Authors

Thet Thet Lin

Kevin Norris

Nicole H. Heppel

Guy Pratt

James M. Allan

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Dr David Allsup D.J.Allsup@hull.ac.uk
Senior Lecturer in Haematology and Honorary Consultant

James Bailey

Robert Hills

Julia W. Grimstead

Rhiannon E. Jones

Bethan Britt-Compton

Chris Fegan

Duncan M. Baird

Chris Pepper

Abstract

© 2014 John Wiley & Sons Ltd. Defining the prognosis of individual cancer sufferers remains a significant clinical challenge. Here we assessed the ability of high-resolution single telomere length analysis (STELA), combined with an experimentally derived definition of telomere dysfunction, to predict the clinical outcome of patients with chronic lymphocytic leukaemia (CLL). We defined the upper telomere length threshold at which telomere fusions occur and then used the mean of the telomere 'fusogenic' range as a prognostic tool. Patients with telomeres within the fusogenic range had a significantly shorter overall survival (P  <  0·0001; Hazard ratio [HR] = 13·2, 95% confidence interval [CI]  = 11·6-106·4) and this was preserved in early-stage disease patients (P  <  0·0001, HR=19·3, 95% CI = 17·8-802·5). Indeed, our assay allowed the accurate stratification of Binet stage A patients into those with indolent disease (91% survival at 10 years) and those with poor prognosis (13% survival at 10 years). Furthermore, patients with telomeres above the fusogenic mean showed superior prognosis regardless of their IGHV mutation status or cytogenetic risk group. In keeping with this finding, telomere dysfunction was the dominant variable in multivariate analysis. Taken together, this study provides compelling evidence for the use of high-resolution telomere length analysis coupled with a definition of telomere dysfunction in the prognostic assessment of CLL.

Journal Article Type Article
Publication Date 2014-10
Journal British journal of haematology
Print ISSN 0007-1048
Electronic ISSN 1365-2141
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 167
Issue 2
Pages 214-223
Institution Citation Lin, T. T., Norris, K., Heppel, N. H., Pratt, G., Allan, J. M., Allsup, D. J., …Pepper, C. (2014). Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease. British journal of haematology, 167(2), 214-223. https://doi.org/10.1111/bjh.13023
DOI https://doi.org/10.1111/bjh.13023
Keywords Telomere length, Telomere fusion, Genomic instability, Leukaemia, Neoplasia
Publisher URL http://onlinelibrary.wiley.com/doi/10.1111/bjh.13023/abstract
Copyright Statement ©2015 University of Hull
Additional Information Author's accepted manuscript of article: Lin, T. T., Norris, K., Heppel, N. H., Pratt, G., Allan, J. M., Allsup, D. J., Bailey, J., Cawkwell, L., Hills, R., Grimstead, J. W., Jones, R. E., Britt-Compton, B., Fegan, C., Baird, D. M. and Pepper, C. (2014), Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease. British Journal of Haematology, 167: 214–223. doi: 10.1111/bjh.13023

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