Bisphosphonate related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in MM
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE11948 | GEO | 2008/09/25
SECONDARY ACCESSION(S): PRJNA105805
REPOSITORIES: GEO
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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).
2008-09-25 | E-GEOD-11948 | biostudies-arrayexpress
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.
2008-06-15 | E-GEOD-7116 | biostudies-arrayexpress
Project description:Objectives: Osteonecrosis of the jaw (ONJ), a necrotic bone disease unique to the craniofacial region, is often observed among cancer patients treated with bisphosphonate (BP)-based chemotherapy and becomes a costly and debilitating source of pain and reduced quality of life. Elucidation of clinicopathological mechanism and biomarkers of ONJ that can indicate probable disease course would allow for better assessment of treatment strategies for individual patients. To address our overall goal of identifying novel diagnostic and prognostic strategies for ONJ, this study specifically aims to understand the alendronate (ALN) treatment-induced perturbation of bone proteome and microenvironmental pathophysiology of ONJ using targeted molecular analyses and computational approaches based on an in vitro cell culture system. This study also focuses on identifying proteome perturbation and potential molecular biomarkers during ONJ development. Methods: To understand the molecular mechanisms underlying ONJ, an unbiased and global proteomics approach combined with big data analysis using bioinformatics was applied. Biochemical and functional analyses were followed to tease out the mechanisms regulated by ALN treatment. Results: The current findings from our global proteomics study and biochemical analyses suggested that the RIPK3/Wnt/GSK3/β-catenin signaling pathway is significantly perturbed upon alendronate treatment, resulting in abnormal angiogenesis/inflammation/bone anabolism/remodeling/bone mineralization in the in vitro cell culture system. Conclusion: This investigation on potential key signaling mechanisms underlying ONJ will provide a rational basis for suppressing BP-induced ONJ and novel therapeutic strategies against ONJ.
2021-09-10 | PXD024585 | Pride
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. Keywords: Therapy complication analysis
2007-11-29 | GSE7116 | GEO
Project description:Single nucleotide polymorphisms (SNPs) of factor V Leiden have been associated with osteonecrosis of the femoral head (ONFH) in Caucasians but remains controversial in Asians. We used an SNP microarray to screen 55 loci of factor V gene in patients with ONFH of Chinese. Significantly different candidate SNPs at 14 loci were analyzed in 146 patients and 116 healthy controls using MALDI-TOF (matrix-assisted laser desorption/ionization time-of-flight) mass spectrometry and gene sequencing. The factor V Leiden (rs6025) was not found in all participants. Six SNP loci (rs9332595, rs6020, rs9332647, rs3766110, rs10919186, and rs12040141) were confirmed with significant differences in patients but not in controls. The rs6020 G-to-A polymorphism was found in 88.9% of the patients. In addition, a high percentage (84.7%) of the patients had an abnormal coagulation profile that included hyperfibrinogen, elevated fibrinogen degradation products, elevated D-dimer, abnormal protein S, abnormal protein C, or a decrease in anti-thrombin III. Patients with the rs6020 G-to-A polymorphism (mutation) had a higher risk (odds ratio: 4.33; 95% confidence interval: 1.36-13.76) of having coagulation abnormalities than did those without the mutation (wild-type) (p = 0.008). Our findings suggested that the rs6020 polymorphism might be the genetic trait that accounts for the higher prevalence of ONFH in the Chinese population than in Westerners. Exposure to risk factors such as alcohol and steroids in patients with the rs6020 polymorphism causes coagulation abnormalities and, subsequently, thromboembolisms in the femoral head. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from peripheral blood samples. SNP genotype analysis of Affymetrix 6.0 Chip. SNP arrays was performed for 22 Chinese patients with Osteonecrosis of the Femoral Head.
2014-07-28 | E-GEOD-58951 | biostudies-arrayexpress
Project description:Single nucleotide polymorphisms (SNPs) of factor V Leiden have been associated with osteonecrosis of the femoral head (ONFH) in Caucasians but remains controversial in Asians. We used an SNP microarray to screen 55 loci of factor V gene in patients with ONFH of Chinese. Significantly different candidate SNPs at 14 loci were analyzed in 146 patients and 116 healthy controls using MALDI-TOF (matrix-assisted laser desorption/ionization time-of-flight) mass spectrometry and gene sequencing. The factor V Leiden (rs6025) was not found in all participants. Six SNP loci (rs9332595, rs6020, rs9332647, rs3766110, rs10919186, and rs12040141) were confirmed with significant differences in patients but not in controls. The rs6020 G-to-A polymorphism was found in 88.9% of the patients. In addition, a high percentage (84.7%) of the patients had an abnormal coagulation profile that included hyperfibrinogen, elevated fibrinogen degradation products, elevated D-dimer, abnormal protein S, abnormal protein C, or a decrease in anti-thrombin III. Patients with the rs6020 G-to-A polymorphism (mutation) had a higher risk (odds ratio: 4.33; 95% confidence interval: 1.36-13.76) of having coagulation abnormalities than did those without the mutation (wild-type) (p = 0.008). Our findings suggested that the rs6020 polymorphism might be the genetic trait that accounts for the higher prevalence of ONFH in the Chinese population than in Westerners. Exposure to risk factors such as alcohol and steroids in patients with the rs6020 polymorphism causes coagulation abnormalities and, subsequently, thromboembolisms in the femoral head.
2014-07-28 | GSE58951 | GEO
Project description:We recently showed that microRNA different profile from Trauma-induced osteonecrosis of the femoral head (TIONFH) and healing patients.
2017-09-14 | GSE89587 | GEO
Project description:Bisphosphonate related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in MM
| PRJNA105805 | ENA
Project description:Purpose of reviewOsteonecrosis of the jaw (ONJ) is an uncommon condition noted to occur in patients with cancer who are receiving intravenous bisphosphonates. The cause of ONJ remains unknown. The leading hypotheses addressing the mechanism of ONJ are reviewed here.Recent findingsThe present clinical data suggest that ONJ may occur in approximately 5% of patients with metastatic bone disease. The ability to predict an individual's risk of developing ONJ remains elusive. It is likely that an altered bone microenvironment and/or host defense mechanisms effected by medications used to treat patients with metastatic bone disease contributes to the development of ONJ. Medications that significantly reduce osteoclastic activity are associated with ONJ. Preclinical models of ONJ are being developed but to establish such an intricate systemic condition in animals is challenging.SummaryThe ONJ field has progressed via knowledge gained by case reports, population-based studies, and emerging animal models. Still, there are myths that need to be resolved and important clues that need to be investigated. Understanding the pathophysiology of this condition will be critical to improve patient care. Communications between oncologists, dentists, basic scientists, and patients are central to effective treatment and research for this condition.
| S-EPMC2962852 | biostudies-literature
Project description:Purpose: The goal of this study was to characterize the gingival oral barrier immunity of bisphosphonate-related osteonecrosis of the jaw (BRONJ) and HMDP-treated BRONJ mouse maxilla. Method: Mouse BRONJ was induced by Zoledronate IV injection and maxillary left first molar extraction. HMDP-DNV was topically applied to the BRONJ lesion 2 times. Mouse palatal gingiva was harvested 2 weeks after tooth extraction. Gingival cells were harvested and subjected to 10X Genomix scRNA-seq. Cell Ranger processed data were analysed.
2022-01-08 | GSE193110 | GEO