TY - JOUR
T1 - Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping
AU - Johnson, David C.
AU - Corthals, Sophie
AU - Ramos, Christine
AU - Hoering, Antje
AU - Cocks, Kim
AU - Dickens, Nicholas J.
AU - Haessler, Jeff
AU - Goldschmidt, Harmut
AU - Child, J. Anthony
AU - Bell, Sue E.
AU - Jackson, Graham
AU - Baris, Dalsu
AU - Rajkumar, S. Vincent
AU - Davies, Faith E.
AU - Durie, Brian G.M.
AU - Crowley, John
AU - Sonneveld, Pieter
AU - Van Ness, Brian
AU - Morgan, Gareth J.
PY - 2008/12/15
Y1 - 2008/12/15
N2 - A venous thromboembolism (VTE) with the subsequent risk of pulmonary embolism isamajor concernin the treatment of patients with multiple myeloma with tha-lidomide. 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. Patients and controls were taken from 3 large clinical trials: Medical Research Council (MRC) Myeloma IX, Hovon-50, and Eastern Cooperative Oncology Group (ECOG) EA100, which compared conventional treatments with thalidomide in patients with myeloma. 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 micro-environment, and the endothelium. The clinical trials described in this paper have been registered as follows: MRC Myeloma IX: ISRCTN68454111; Hovon-50: NCT00028886; and ECOG EA100: NCT00033332.
AB - A venous thromboembolism (VTE) with the subsequent risk of pulmonary embolism isamajor concernin the treatment of patients with multiple myeloma with tha-lidomide. 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. Patients and controls were taken from 3 large clinical trials: Medical Research Council (MRC) Myeloma IX, Hovon-50, and Eastern Cooperative Oncology Group (ECOG) EA100, which compared conventional treatments with thalidomide in patients with myeloma. 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 micro-environment, and the endothelium. The clinical trials described in this paper have been registered as follows: MRC Myeloma IX: ISRCTN68454111; Hovon-50: NCT00028886; and ECOG EA100: NCT00033332.
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U2 - 10.1182/blood-2008-02-140434
DO - 10.1182/blood-2008-02-140434
M3 - Article
C2 - 18805967
AN - SCOPUS:58149380751
SN - 0006-4971
VL - 112
SP - 4924
EP - 4934
JO - Blood
JF - Blood
IS - 13
ER -