Project description:BACKGROUND:; Osteonecrosis of the jaw (ONJ) has been reported in patients with a history of aminobisphosphonate use. METHODS:; In order to define ONJ and gain insights into its pathophysiology, clinical, radiographic, biochemical, and microarray profiling studies were conducted in 11 patients with multiple myeloma (MM) and ONJ. RESULTS:; Eleven patients between the ages of 57 and 81 yrs were treated with either pamidronate (n=3), zoledronate (n=4), or both agents sequentially (n=4) for a mean of 38.7 months. Radiographic studies demonstrated radiolucency and sclerosis on plain films. Functional imaging with positron emission tomography (PET) demonstrated a visual increase in glucose metabolism and mineralization at sites of ONJ, using fluorodeoxyglucose (FDG) and sodium fluoride (NaF), respectively. Quantitative regional analysis confirmed an increased standardized uptake value (SUVmax) in areas of ONJ. The target to background ratio of SUVmax was significantly greater for NaF-PET than FDG-PET scans, suggesting that NaF-PET may provide superior image quality for identifying ONJ. Transcriptional profiling of peripheral blood mononuclear cells (PBMCs) using the Affymetrix U133Plus 2.0 gene chip in all 11 MM patients compared with 10 age matched MM controls and 5 healthy volunteers demonstrated that genes involved in osteoblast and osteoclast signaling cascades were significantly downregulated in patients with ONJ, as were proteins confirmed by ELISA. CONCLUSIONS:; ONJ is seen in patients with a history of aminobisphosphonate use. Functional imaging with NaF PET confirms the diagnosis of ONJ. Gene and protein studies are consistent with altered bone remodeling, evidenced by suppression of both bone resorption and formation. Experiment Overall Design: Transcriptional profiling of peripheral blood mononuclear cells (PBMCs) was performed using the Affymetrix U133Plus 2.0 Gene Chip (Affymetrix, Santa Clara, CA, USA) in 11 patients with osteonecrosis of the jaw and multiple myeloma and compared with the profiles of the 10 myeloma patients on bisphosphonate therapy without osteonecrosis of the jaw and 5 healthy volunteers.

Project description:We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients under bisphosphonate therapy. A genome wide association study was performed using 500.568 single nucleotide polymorphisms (SNPs) in two series of homogeneously treated MM patients: one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four SNPs (rs1934951, rs1934980, rs1341162 and rs17110453) mapped within the Cytochrome P450-2C gene (CYP2C8) showed a different distribution between cases and controls with statistically significant differences (p=1.07x10-6, p=4.231x10-6, p=6.22x10-6 and p=2.15x10-5, respectively). SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni correction (P corrected value=0.02). Genotyping results displayed an overrepresentation of the T allele in cases as compared with controls (48% vs. 12%). Thus, individuals homozygous for the T allele had an increased likelihood of developing ONJ (Odds ratio 12.75, 95% confidence interval 3.7 to 43.5). We studied 22 cases (MM with ONJ) and 65 controls (MM without ONJ), matched for age, gender and ethnicity (note: all of the cases and controls are Caucasian). All patients were enrolled in the GEM-00 protocol, which consists on polychemotherapy and autologous transplantation. All received BPs therapy, either Pamidronate (16 cases, 57 controls) or Zoledronic Acid (6 cases, 8 controls) planned for 2 years (median 22 months, range 9-24 months). Clinical characteristics were similar between controls and cases. Study protocols were approved by the ethics committee and written informed consent was obtained from all participants. Each patient was genotyped using the Affymetrix GeneChip Mapping 500K set of microarrays (Affymetrix, Santa Clara, CA) according to the manufacturer’s recommendations. Genotypes were determined using the BRLMM algorithm with cases and controls undergoing joint cluster analysis, after ensuring a robust association test through quality filtering tests. Based on stringent quality control criteria a total of 339.972 SNPs were selected for subsequent analyses. Criteria for exclusion were: 1) call rate<90%, 2) minor allele frequency <5% and 3) deviations from Hardy-Weinberg equilibrium with a p<0.00001. Sexual chromosomes were excluded for analysis. To test for allelic associations between SNPs and ONJ, we constructed 2x2 contingency tables and compared using the two-sided Fisher’s exact or Chisquare tests through SPSS software (SPSS 14.0, Inc. Chicago, IL, USA). P-values were corrected (Pc) using the Bonferroni correction. The strength of association was estimated by the odds ratio (OR), and their 95% confidence intervals (CI) were calculated by Cornfield methods. Linkage disequilibrium between SNPs was analyzed using the Arlequin Software (http://anthro.unige.ch/arlequin).

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