Published Ahead of Print on June 9, 2011, as doi:10.3324/haematol.2011.043471. Copyright 2011 Ferrata Storti Foundation.
Early Release Paper
Association between SNP-genotype and chronic lymphocytic leukemia outcome in a randomized chemotherapy trial by Rachel Wade, Maria Chiara Di Bernardo, Sue Richards, Davide Rossi, Dalemari Crowther-Swanepoel, Gianluca Gaidano, David G. Oscier, Daniel Catovsky, and Richard S. Houlston Haematologica 2011 [Epub ahead of print] Citation: Wade R, Di Bernardo MC, Richards S, Rossi D, Crowther-Swanepoel D, Gaidano G, Oscier DG, Catovsky D, and Houlston RS. Association between SNP-genotype and chronic lymphocytic leukemia outcome in a randomized chemotherapy trial. Haematologica. 2011; 96:xxx doi:10.3324/haematol.2011.043471 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process. Haematologica (pISSN: 0390-6078, eISSN: 1592-8721, NLM ID: 0417435, www.haematologica.org) publishes peer-reviewed papers across all areas of experimental and clinical hematology. The journal is owned by the Ferrata Storti Foundation, a non-profit organization, and serves the scientific community with strict adherence to the principles of open access publishing (www.doaj.org). In addition, the journal makes every paper published immediately available in PubMed Central (PMC), the US National Institutes of Health (NIH) free digital archive of biomedical and life sciences journal literature.
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DOI: 10.3324/haematol.2011.043471
Association between SNP-genotype and chronic lymphocytic leukemia outcome in a randomized chemotherapy trial Running title: SNPs and chronic lymphocytic leukemia prognosis
Rachel Wade1*, Maria Chiara Di Bernardo2*, Sue Richards1, Davide Rossi3, Dalemari Crowther-Swanepoel2, Gianluca Gaidano3, David G. Oscier4, Daniel Catovsky5 and Richard S. Houlston2 1
Clinical Trial Service Unit, University of Oxford, Oxford, OX3 7LF, UK; 2Section of Cancer
Genetics, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK; 3Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont,
Novara,
Italy;
4
Department
of
Haematology,
Royal
Bournemouth
Hospital,
Bournemouth, Dorset, UK, and 5Section of Haemato-Oncology, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK *RW and MCDB contributed equally to this manuscript
Key words: chronic lymphocytic leukemia, SNP, chlorambucil, fludarabine, cyclophosphamide.
Acknowledgments The authors would like to thank all patients and clinicians participating in the LRF CLL-4 trial.
Funding This work was primarily supported by a grant from Leukaemia Research and the MRC (G8223452). Additional funding was provided by the Arbib Foundation and Cancer Research UK.
Correspondence Richard S. Houlston, Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK. Phone: international +44.020.87224175. Fax: international +44.020.87224059. E-mail:
[email protected]
1
DOI: 10.3324/haematol.2011.043471
ABSTRACT
Background. There is variability in patient outcome from chronic lymphocytic leukaemia for apparently same-stage disease. Identifying genetic variants that influence patient outcome and response to treatment may provide important insight into the biology of the disease. Design and Methods. We investigated the possibility that genetic variation influences outcome by conducting a genome-wide analysis of 346,831 single nucleotide polymorphisms in 356 patients entered into a phase III trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Genotypes were linked to individual patient outcome data and response to chemotherapy. The association between genotype and progression free survival was assessed by Cox regression analysis adjusting for treatment and clinicopathology. Results. The strongest associations were shown for rs1949733 (ACOX3; P=8.22x10-7), rs1342899 (P=7.72x10-7) and rs11158493 (PPP2R5E; P=8.50x10-7). In addition among the 52 single nucleotide polymorphisms associated at P
