Genetic polymorphisms of EPHX1, Gsk3beta, TNFSF8 and myeloma cell DKK-1 expression linked to bone disease in myeloma.
Bone disease in myeloma occurs as a result of complex interactions between myeloma cells and the bone marrow microenvironment. A custom-built DNA single nucleotide polymorphism (SNP) chip containing 3404 SNPs was used to test genomic DNA from myeloma patients classified by the extent of bone disease. Correlations identified with a Total Therapy 2 (TT2) (Arkansas) data set were validated with Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group (SWOG) data sets. Univariate correlates with bone disease included: EPHX1, IGF1R, IL-4 and Gsk3beta. SNP signatures were linked to the number of bone lesions, log(2) DKK-1 myeloma cell expression levels and patient survival. Using stepwise multivariate regression analysis, the following SNPs: EPHX1 (P=0.0026); log(2) DKK-1 expression (P=0.0046); serum lactic dehydrogenase (LDH) (P=0.0074); Gsk3beta (P=0.02) and TNFSF8 (P=0.04) were linked to bone disease. This assessment of genetic polymorphisms identifies SNPs with both potential biological relevance and utility in prognostic models of myeloma bone disease.
Durie
B G M
BG
Hematology/Oncology, Cedars-Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer Institute & Aptium Oncology, Los Angeles, CA 90048, USA. bdurie@aptiumoncology.com
Van Ness
B
B
Ramos
C
C
Stephens
O
O
Haznadar
M
M
Hoering
A
A
Haessler
J
J
Katz
M S
MS
Mundy
G R
GR
Kyle
R A
RA
Morgan
G J
GJ
Crowley
J
J
Barlogie
B
B
Shaughnessy
J
J
D014408:Biomarkers, Tumor / Q000235:genetics; D001847:Bone Diseases / Q000235:genetics*; D053285:CD30 Ligand / Q000235:genetics*; D017326:Clinical Trials, Phase III as Topic; D004851:Epoxide Hydrolases / Q000235:genetics*; D020869:Gene Expression Profiling; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D009101:Multiple Myeloma / Q000150:complications / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D015996:Survival Rate
D014408:Biomarkers, Tumor; D053285:CD30 Ligand; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C505774:TNFSF8 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human