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Blood, 15 December 2008, Vol. 112, No. 13, pp. 4924-4934.
Prepublished online as a Blood First Edition Paper on September 19, 2008; DOI 10.1182/blood-2008-02-140434.
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Submitted February 22, 2008
Accepted August 24, 2008
Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping
David C Johnson, Sophie Corthals, Christine Ramos, Antje Hoering, Kim Cocks, Nicholas J Dickens, Jeff Haessler, Harmut Goldschmidt, J. Anthony Child, Sue E Bell, Graham Jackson, Dalsu Baris, S. Vincent Rajkumar, Faith E Davies, Brian G.M. Durie, John Crowley, Pieter Sonneveld, Brian Van Ness, and Gareth J Morgan*
Institute of Cancer Research, London, United Kingdom
Erasmus Medical Center, Rotterdam, Netherlands
University of Minnesota, Minneapolis, MN, United States
Cancer Research and Biostatistics (CRAB), Seattle, WA, United States
University of Leeds, Leeds, United Kingdom
University of Heidelberg, Heidelberg, Germany
University of Newcastle, Newcastle, United Kingdom
National Cancer Institute, Bethesda, MD, United States
Mayo Clinic, Rochester, MN, United States
Cedars-Sinai Medical Center, Los Angeles, CA, United States
* Corresponding author; email: gareth.morgan{at}icr.ac.uk.
A venous thromboembolism (VTE) with the subsequent risk of pulmonary embolism is a major concern in the treatment of multiple myeloma patients with thalidomide. The susceptibility to developing a VTE in response to thalidomide therapy is likely to be influenced by both genetic and environmental factors. To test genetic variation associated with treatment related VTE in patient peripheral blood DNA, we used a custom-built molecular inversion probe (MIP) based single nucleotide polymorphism (SNP) chip containing 3404 SNPs. SNPs on the chip were selected in "functional regions" within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response and side effects associated with myeloma therapy. Cases and controls were taken from three large clinical trials: MRC Myeloma IX, Hovon-50 and ECOG EA100, which compared conventional treatments with thalidomide in myeloma patients. Our analysis showed that the set of SNPs associated with thalidomide-related VTE were enriched in genes and pathways important in drug transport/metabolism, DNA repair and cytokine balance. The effects of the SNPs associated with thalidomide related VTE may be functional at the level of the tumor cell, the tumor-related microenvironment, and the endothelium. The clinical trials described in this paper have been registered as follows: MRC Myeloma IX: ISRCTN68454111, HOVON50: www.clinicaltrials.gov under identifier NCT00028886, and ECOG EA100: www.clinicaltrials.gov under identifier NCT00033332.
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