Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping.
A venous thromboembolism (VTE) with the subsequent risk of pulmonary embolism is a major concern in the treatment of patients with multiple myeloma 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. 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 microenvironment, 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.
Johnson
David C
DC
Section of Haemato-Oncology, Institute of Cancer Research, London, United Kingdom;
Corthals
Sophie
S
Ramos
Christine
C
Hoering
Antje
A
Cocks
Kim
K
Dickens
Nicholas J
NJ
Haessler
Jeff
J
Goldschmidt
Harmut
H
Child
J Anthony
JA
Bell
Sue E
SE
Jackson
Graham
G
Baris
Dalsu
D
Rajkumar
S Vincent
SV
Davies
Faith E
FE
Durie
Brian G M
BG
Crowley
John
J
Sonneveld
Pieter
P
Van Ness
Brian
B
Morgan
Gareth J
GJ
D016022:Case-Control Studies; D002986:Clinical Trials as Topic; D016207:Cytokines; D004260:DNA Repair / Q000235:genetics; D003625:Data Collection; D020869:Gene Expression Profiling; D006487:Hemostasis / Q000235:genetics; D006801:Humans; D009101:Multiple Myeloma / Q000150:complications* / Q000188:drug therapy; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D013792:Thalidomide / Q000009:adverse effects*; D020246:Venous Thrombosis / Q000139:chemically induced* / Q000235:genetics*
D016207:Cytokines; D004364:Pharmaceutical Preparations; D013792:Thalidomide