Frequent ZNF217 mutations lead to transcriptional deregulation of interferon signal transduction via altered chromatin accessibility in B cell lymphoma

Recent exome-wide studies discovered frequent somatic mutations in the epigenetic modifier ZNF217 in primary mediastinal B cell lymphoma (PMBCL) and related disorders. As functional consequences of ZNF217 alterations remain unknown, we comprehensively evaluated their impact in PMBCL. Targeted sequencing identified genetic lesions affecting ZNF217 in 33% of 157 PMBCL patients. Subsequent gene expression profiling (n = 120) revealed changes in cytokine and interferon signal transduction in ZNF217-aberrant PMBCL cases. In vitro, knockout of ZNF217 led to changes in chromatin accessibility interfering with binding motifs for crucial lymphoma-associated transcription factors. This led to disturbed expression of interferon-responsive and inflammation-associated genes, altered cell behavior, and aberrant differentiation. Mass spectrometry demonstrates that ZNF217 acts within a histone modifier complex containing LSD1, CoREST and HDAC and interferes with H3K4 methylation and H3K27 acetylation. Concluding, our data suggest non-catalytic activity of ZNF217, which directs histone modifier complex function and controls B cell differentiation-associated patterns of chromatin structure

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Screening for copy-number alterations and loss of heterozygosity in chronic lymphocytic leukemia--a comparative study of four differently designed, high resolution microarray platforms

Screening for gene copy-number alterations (CNAs) has improved by applying genome-wide microarrays, where SNP arrays also allow analysis of loss of heterozygozity (LOH). We here analyzed 10 chronic lymphocytic leukemia (CLL) samples using four different high-resolution platforms: BAC arrays (32K), oligonucleotide arrays (185K, Agilent), and two SNP arrays (250K, Affymetrix and 317K, Illumina). Cross-platform comparison revealed 29 concordantly detected CNAs, including known recurrent alterations, which confirmed that all platforms are powerful tools when screening for large aberrations. However, detection of 32 additional regions present in 2-3 platforms illustrated a discrepancy in detection of small CNAs, which often involved reported copy-number variations. LOH analysis using dChip revealed concordance of mainly large regions, but showed numerous, small nonoverlapping regions and LOH escaping detection. Evaluation of baseline variation and copy-number ratio response showed the best performance for the Agilent platform and confirmed the robustness of BAC arrays. Accordingly, these platforms demonstrated a higher degree of platform-specific CNAs. The SNP arrays displayed higher technical variation, although this was compensated by high density of elements. Affymetrix detected a higher degree of CNAs compared to Illumina, while the latter showed a lower noise level and higher detection rate in the LOH analysis. Large-scale studies of genomic aberrations are now feasible, but new tools for LOH analysis are requested

Replacement of teeth exhibiting periapical pathology by immediate implants: a prospective, controlled clinical trial

OBJECTIVES: The aim of the present study was to test whether or not immediate implantation leads to more biological complications, when performed at extraction sockets of teeth exhibiting periapical pathology compared with teeth not exhibiting periapical pathology. MATERIALS AND METHODS: In 17 consecutively admitted patients, immediate implant placement was planned in order to replace single teeth exhibiting periapical pathology (test group). These teeth demonstrated pain, periapical radiolucency, fistula, suppuration or a combination of these findings. Another 17 consecutively admitted patients in need of single tooth replacement in the absence of periapical pathology served as the control group. Implant placement and accompanying bone regeneration were performed according to standard clinical procedures. Implants were loaded after a healing period of 3 months. Clinical and radiographical parameters were assessed at the time of implant placement (baseline) and at 12 months thereafter. RESULTS: Out of the 34 patients, four test and one control patient had to be withdrawn from the study due to the inability to obtain primary implant stability. The residual 29 implants revealed a survival rate of 100% 1 year after placement. Clinical and radiographical differences between 12 months and baseline comparing test and control groups showed no statistical significances for any of the parameters assessed. Within test and control groups there was a statistically significant loss of vertical bone height at the adjacent teeth (mesial test=0.4+/-0.6 mm, control=0.4+/-0.5 mm; distal test=0.3+/-0.2 mm, control=0.7+/-0.8 mm) as well as at the implant site (mesial test=1.9+/-1.4 mm, control=1.8+/-1.1 mm; distal test=1.7+/-1.4 mm, control=1.6+/-1.1 mm) and of buccal keratinized mucosa (test=-2.2+/-1.2 mm; control=-1.3+/-1.6 mm) between baseline and 12 months. During the first 13 weeks of healing, two sites of the test and one site of the control group showed signs of infection, which required intervention. Neither the incident of early exit nor of signs of infection was statistically significantly different between the test and the control group (Mann-Whitney U test). CONCLUSION: It is concluded that for those implants where primary stability was achieved, the immediate implant placement performed at extraction sockets exhibiting periapical pathology did not lead to an increased rate of complications and rendered an equally favorable type of tissue integration of the implants in both groups. Implant placement into such sites can, therefore, be successfully performed