Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients

Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a multi‐institutional genome‐wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time‐to‐event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease. The results were combined across the European and Brazilian case sets using a random‐effects meta‐analysis. The strongest association after meta‐analysis was for rs3765555 at 9p24.1, which was inversely associated with overall survival (HR = 1.76; 95% CI 1.41–2.18, p = 4.84 × 10−7). After imputation across this region, the combined analysis identified two SNPs that reached genome‐wide significance. The strongest single association was with rs55933544 (HR = 1.9; 95% CI 1.5–2.4; p = 1.3 × 10−8), which localizes to the GLDC gene, adjacent to the IL33 gene and was consistent across both the European and Brazilian case sets. Using publicly available data, the risk allele was associated with lower expression of IL33 and low expression of IL33 was associated with poor survival in an independent set of patients with osteosarcoma. In conclusion, we have identified the GLDC/IL33 locus on chromosome 9p24.1 as associated with overall survival in patients with osteosarcoma. Further studies are needed to confirm this association and shed light on the biological underpinnings of this susceptibility locus

Polyoma Virus-Induced Osteosarcomas in Inbred Strains of Mice: Host Determinants of Metastasis

The mouse polyoma virus induces a broad array of solid tumors in mice of many inbred strains. In most strains tumors grow rapidly but fail to metastasize. An exception has been found in the Czech-II/Ei mouse in which bone tumors metastasize regularly to the lung. These tumors resemble human osteosarcoma in their propensity for pulmonary metastasis. Cell lines established from these metastatic tumors have been compared with ones from non-metastatic osteosarcomas arising in C3H/BiDa mice. Osteopontin, a chemokine implicated in migration and metastasis, is known to be transcriptionally induced by the viral middle T antigen. Czech-II/Ei and C3H/BiDa tumor cells expressed middle T and secreted osteopontin at comparable levels as the major chemoattractant. The tumor cell lines migrated equally well in response to recombinant osteopontin as the sole attractant. An important difference emerged in assays for invasion in which tumor cells from Czech-II/Ei mice were able to invade across an extracellular matrix barrier while those from C3H/BiDa mice were unable to invade. Invasive behavior was linked to elevated levels of the metalloproteinase MMP-2 and of the transcription factor NFAT. Inhibition of either MMP-2 or NFAT inhibited invasion by Czech-II/Ei osteosarcoma cells. The metastatic phenotype is dominant in F1 mice. Osteosarcoma cell lines from F1 mice expressed intermediate levels of MMP-2 and NFAT and were invasive. Osteosarcomas in Czech-II/Ei mice retain functional p53. This virus-host model of metastasis differs from engineered models targeting p53 or pRb and provides a system for investigating the genetic and molecular basis of bone tumor metastasis in the absence of p53 loss

Genome-wide Association Study Identifies Two Susceptibility Loci for Osteosarcoma

Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. In order to better understand the genetic etiology of osteosarcoma, we performed a multi-stage genome-wide association study (GWAS) consisting of 941 cases and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: rs1906953 at 6p21.3, in the glutamate receptor metabotropic 4 [GRM4] gene (P = 8.1 ×10-9), and rs7591996 and rs10208273 in a gene desert on 2p25.2 (P = 1.0 ×10-8 and 2.9 ×10-7). These two susceptibility loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma

Expression analysis of genes associated with human osteosarcoma tumors shows correlation of RUNX2 overexpression with poor response to chemotherapy

Background: Human osteosarcoma is the most common pediatric bone tumor. There is limited understanding of the molecular mechanisms underlying osteosarcoma oncogenesis, and a lack of good diagnostic as well as prognostic clinical markers for this disease. Recent discoveries have highlighted a potential role of a number of genes including: RECQL4, DOCK5, SPP1, RUNX2, RB1, CDKN1A, P53, IBSP, LSAMP, MYC, TNFRSF1B, BMP2, HISTH2BE, FOS, CCNB1, and CDC5L. Methods: Our objective was to assess relative expression levels of these 16 genes as potential biomarkers of osteosarcoma oncogenesis and chemotherapy response in human tumors. We performed quantitative expression analysis in a panel of 22 human osteosarcoma tumors with differential response to chemotherapy, and 5 normal human osteoblasts.Results: RECQL4, SPP1, RUNX2, and IBSP were significantly overexpressed, and DOCK5, CDKN1A, RB1, P53, and LSAMP showed significant loss of expression relative to normal osteoblasts. In addition to being overexpressed in osteosarcoma tumor samples relative to normal osteoblasts, RUNX2 was the only gene of the 16 to show significant overexpression in tumors that had a poor response to chemotherapy relative to good responders. Conclusion: These data underscore the loss of tumor suppressive pathways and activation of specific oncogenic mechanisms associated with osteosarcoma oncogenesis, while drawing attention to the role of RUNX2 expression as a potential biomarker of chemotherapy failure in osteosarcoma. © 2010 Sadikovic et al; licensee BioMed Central Ltd

Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors

Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors. We explored how and when EWSR1-ETS fusions arise by studying the whole genomes of Ewing sarcomas. In 52 of 124 (42%) of tumors, the fusion gene arises by a sudden burst of complex, loop-like rearrangements, a process called chromoplexy, rather than by simple reciprocal translocations. These loops always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions. Similar loops forming canonical fusions were found in three other sarcoma types. Chromoplexy-generated fusions appear to be associated with an aggressive form of Ewing sarcoma. These loops arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel

Genome-wide association study identifies two susceptibility loci for osteosarcoma

Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 × 10⁻⁹) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 × 10⁻⁸ and 2.9 × 10⁻⁷, respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma

springs, southern Turkey

The Dalaman and Koycegiz thermal springs are from karstic limestones belonging to Upper Cretaceous to Burdigalian Beydaglan autochthon and Carboniferous to Lutetian Lycian nappes. They have measured temperatures of 24- 41 degrees C, specific electrical conductivities of 14,310-45,600 mu S/cm, and are dominated by Na (1550-8500 mg/kg) and Cl (2725-15,320 mg/kg). The heat source of the geothermal systems of the area is tectonic related and the occurrence of the thermal springs is related to the young normal faults. Meteoric waters and seawaters recharge the reservoir rocks, are heated at depth with increasing geothermal gradient, and move up to the surface through the fractures and faults by convection trend and emerge as thermal springs. While thermal waters move up to the surface, they mix with different proportions of seawater and cold fresh waters. The seawater contribution to the thermal waters varies from 24% to 78%. Lake waters in the area are connected with thermal waters. Consequently, their chemical composition is influenced by the chemistry of thermal waters. Chemical equilibrium modelling based on measured outlet temperatures and measured pH shows that all the waters are oversaturated with respect to quartz and K-mica and undersaturated with respect to AI(OH)(3), anorthite, gypsum, siderite and SiO2(a). Albite, alunite, aragonite, Ca-montmorillonite, calcite, chalcedony, chlorite, dolomite, Fe(OH)(3)(a), fluorite, gypsum, illite, K-feldspar, kaolinite and sepiolite minerals are mostly oversaturated or undersaturated. Mineral saturation studies of the thermal springs indicate that dolomite, chalcedony and quartz are most likely to cause scaling at outlet conditions. Assessments from various chemical geothermometers, and Na-K-Mg ternary and mineral equilibrium diagrams suggest that the reservoir temperature is around 65-90 degrees C. The temperatures obtained from quartz, quartz-steam loss, Mg/Li geothermometers and mineral equilibrium diagrams give the most reasonable results. (c) 2005 Elsevier Ltd. All rights reserved

Effects of oral isotretinoin therapy on the nasal cavities.

INTRODUCTION: Isotretinoin (13 cis-retinoic acid) is the most effective treatment for acne vulgaris and is the only treatment option that can provide either remission or a permanent cure. OBJECTIVE: The aim of this study was to use both subjective and objective methods to assess the nasal complaints of patients with severe acne who received oral isotretinoin therapy. METHODS: Fifty-four subjects were enrolled in the study. All the subjects were assessed with subjective (NOSE and VAS questionnaires) and objective (rhinomanometry and saccharine) tests to determine the severity of their nasal complaints. RESULTS: The mean severity scores (min: 0; max: 100) for nasal dryness/crusting and epistaxis were 0.47 ± 1.48 (0–5); 0.35 ± 1.30 (0–5) at admission, 3.57 ± 4.45 (0–10); 2.26 ± 4.71 (0–20) at the first month, and 4.28 ± 6 (0–20); 2.26 ± 4.71 (0–20) at the third month of the treatment respectively. Total nasal resistance of 0.195 ± 0.079 (0.12–0.56) Pa/cm(3)/s at admission, 0.21 ± 0.084 (0.12–0.54) Pa/cm(3)/s at the first month, and 0.216 ± 0.081 (0.14–0.54) Pa/cm(3)/s at the third month. CONCLUSION: Oral isotretinoin therapy can cause the complaint of nasal obstruction. In addition, nasal complaints, such as dryness/crusting and epistaxis, significantly increase in patients during the therapy schedule

Public Health Reports ; v. 107 , no. 3 : cover

1992701