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| |  DNA Amplification and Elevated CKS1B Expression Associated With Poor Survival in Multiple Myeloma: Presented at ICML By Chris Berrie LUGANO, SWITZERLAND -- June 10, 2005 -- A gene expression signature of 70 genes that involves predominantly chromosome 1, and which includes the 1q21 amplicon of the critical modulator of cell cycle progression CSK1B, helps identify patients with multiple myeloma (MM) who are at high risk of rapid death, according to a study reported here June 8th at the 9th International Conference on Malignant Lymphoma (ICML). "Patients with myeloma experience a high degree of variability in survival, and the molecular mechanisms of these variations have not been completely explained," said John Shaughnessy, PhD, associate professor of medicine, and director, Lanbert Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States. Dr. Shaughnessy and colleagues conducted their study using global gene expression profiling to identify genes related to rapid death on early follow-up in patients with MM. This involved 351 consecutive patients with newly diagnosed MM who went on to be treated with Total Therapy 2, which involved randomisation to thalidomide or no thalidomide in addition to the following regimen: chemotherapy regimen of vincristine, doxorubicin (Adriamycin), and dexamethasone; high-dose cyclophosphamide; chemotherapy regimen of etoposide, dexamethasone, cytarabine (Ara-C), cisplatin (Platinol); melphalan 200 mg/m2; chemotherapy regimen of dexamethasone, cyclophosphamide, etoposide, and cisplatin (Platinol); chemotherapy regimen of cyclophosphamide, doxorubicin (Adriamycin), and dexamethasone. During the mean follow-up period of 30 months, there were 92 events and 61 deaths. CD138-enriched bone marrow plasma cells were obtained from these patients, and they were analysed with gene expression profiling (GEP) using oligonucleotide microarray-based gene expression analysis. Confirmation of the GEP data was obtained using interphase fluorescence in situ hybridisation (FISH), either alone or with GEP, and Western blotting and RNA interference with GEP. Samples from the 351 patients were screened against 54,675 probe sets, and 70 gene candidates were obtained following a log rank test for poor survival of both the under-expressed genes (n = 19; lower quartile of expression versus upper 75%) and the over-expressed genes (n = 51; upper quartile of expression versus lower 75%). Five gene groups were defined by the expression patterns of these 70 genes, with high expression of the group 5 genes representing poor risk in patients. The Kaplan-Meier survival curves based on this model showed that the expression of these group 5 genes resulted in the very rapid death of patients (group 5 vs other groups, P <.00001). All 70 of these genes were then mapped to the human chromosomes, with 30% of 70 mapping to chromosome 1. Following on from previous indications of 1q21 abnormalities involved in poor survival in myeloma, Dr Shaughnessy said, "We then asked ourselves if there were any 1q21 genes in our model, and one of those was CKS1B." Indeed, the quartile expression of this 1 gene alone was a highly significant indicator of poor survival (P =.0001). The use of interphase FISH analysis on 193 of the overall cohort indicated that increases in 1q21 copy number, which was associated with increased CSK1B expression, significantly correlated with poor survival both in a validation cohort (non-GEP) of 224 patients (>/= 4 copies vs 2 or 3 copies; P <.0001) and in the full combined group of 421 patients (193 + 224; P <.0001). Further confirmation demonstrated that the CSK1B expression and proliferation index increases in relapsing myeloma, with an up to 8-fold CSK1B gene amplification revealed in end-stage myeloma. CSK1B is a master regulator of the cyclin-dependent inhibitor p27KIP levels, and this study also demonstrated that CSK1B mRNA and protein levels inversely correlated with p27KIP levels. Moreover, the knockdown of CSK1B expression with RNA interference promoted p27KIP stabilisation and inhibited cell growth. To finish, Dr Shaughnessy stressed that, "It is also important to note that the 1q21 amplification is a common event in virtually all advanced cancers and CSK1B amplification might actually be a universal event in cancer at large."
[Study title: DNA Amplification and Elevated Expression of CKS1B Is Associated With Reduced Levels of P27KIP1 and Poor Survival in Multiple Myeloma. Abstract 009]
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