Familiäre Tumorerkrankungen im Knochen

Zusammenfassung: Familiäre Erkrankungen, die zur Bildung von Knochentumoren führen, sind selten. Sie entwickeln sich im Zusammenhang mit genetischen Alterationen, die den Zellzyklus (Retinoblastomsyndrom/RB1, Li-Fraumeni-Syndrom/p53), wachstumssteuernde Transkriptionskaskaden (Enchondromatose/PTHR1, multiple hereditäre Exostosen/EXT1, EXT2) oder den Erhalt der DNA-Stabilität (Rothmund-Thomson-/RECQL4, Werner-/WRN und Bloom-Syndrom/BLM) betreffen. So entstehen entweder multiple gutartige Tumoren, die sekundär maligne transformieren (Enchondromatosen: Enchondrome; multiple hereditäre Exostosen: Osteochondrome), oder maligne Tumoren, meist Osteosarkome als Primär- (Li-Fraumeni-, Rothmund-Thomson-, Werner- und Bloom-Syndrom) oder Sekundärmanifestation (Retinoblastomsyndrom). Einige dieser Läsionen sind außerdem mit einem erhöhten allgemeinen Tumorrisiko behaftet. Gegenüber sporadisch auftretenden gleichartigen Tumoren bestehen oft Unterschiede in zeitlicher Manifestation, Lokalisation und Histologie, die für die Erkennung des zugrunde liegenden Syndroms hilfreich sein könne

Chondrogene Tumoren des Skeletts

Zusammenfassung: Obwohl das Spektrum gutartiger und bösartiger Knorpeltumoren sehr breit ist, lässt sich unter Berücksichtigung von Alter, Klinik, Lokalisation und Topik im Knochen sowie des Röntgenbefundes in der Regel auch an kleinen Biopsien eine sichere Diagnose stellen. Dies gilt allerdings nur mit Einschränkungen für die Unterscheidung zwischen Enchondromen und Chondrosarkomen Grad1 und setzt insgesamt eine langjährige Erfahrung in der interdisziplinären Knochentumordiagnostik voraus. In Einzelfällen können immunhistochemische Ergebnisse differenzialdiagnostisch weiterhelfen, wenn sie im Kontext der übrigen Befunde interpretiert werden. Wegen der therapeutischen und prognostischen Konsequenzen ist die Zusammenarbeit mit einem Referenzzentrum ratsa

Warthin-Tumor mit Karzinom: Maligne Transformation oder Metastase?

Zusammenfassung: Wir berichten über einen ungewöhnlichen Fall eines langjährig klinisch diagnostizierten Warthin-Tumors (WT) mit plötzlicher Größenzunahme und nachfolgender Resektion. Histologisch konnte der WT bestätigt werden, zeigte jedoch zusätzlich diffuse Infiltrate eines dissolut wachsenden Adenokarzinoms. Unter der Annahme eines maligne transformierten WT wurden radiologische Staging-Untersuchungen angeschlossen, mit deren Hilfe ein metastasierendes Mammakarzinom mit identischer Morphologie zu den WT-Infiltraten entdeckt wurde. Die seltene Diagnose eines maligne transformierten WT erfordert daher immer den Ausschluss eines metastasierten Tumorleiden

How MicroRNA and Transcription Factor Co-regulatory Networks Affect Osteosarcoma Cell Proliferation

Osteosarcomas (OS) are complex bone tumors with various genomic alterations. These alterations affect the expression and function of several genes due to drastic changes in the underlying gene regulatory network. However, we know little about critical gene regulators and their functional consequences on the pathogenesis of OS. Therefore, we aimed to determine microRNA and transcription factor (TF) co-regulatory networks in OS cell proliferation. Cell proliferation is an essential part in the pathogenesis of OS and deeper understanding of its regulation might help to identify potential therapeutic targets. Based on expression data of OS cell lines divided according to their proliferative activity, we obtained 12 proliferation-related microRNAs and corresponding target genes. Therewith, microRNA and TF co-regulatory networks were generated and analyzed regarding their structure and functional influence. We identified key co-regulators comprising the microRNAs miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC in the derived networks. These regulators are implicated in NFKB- and RB1-signaling and focal adhesion processes based on their common or interacting target genes (e.g., CDK6, CTNNB1, E2F4, HES1, ITGA6, NFKB1, NOTCH1, and SIN3A). Thus, we proposed a model of OS cell proliferation which is primarily co-regulated through the interactions of the mentioned microRNA and TF combinations. This study illustrates the benefit of systems biological approaches in the analysis of complex diseases. We integrated experimental data with publicly available information to unravel the coordinated (post)-transcriptional control of microRNAs and TFs to identify potential therapeutic targets in OS. The resulting microRNA and TF co-regulatory networks are publicly available for further exploration to generate or evaluate own hypotheses of the pathogenesis of OS (http://www.complex-systems.uni-muenster.​de/co_networks.html)

Structuring osteosarcoma knowledge: an osteosarcoma-gene association database based on literature mining and manual annotation

Osteosarcoma (OS) is the most common primary bone cancer exhibiting high genomic instability. This genomic instability affects multiple genes and microRNAs to a varying extent depending on patient and tumor subtype. Massive research is ongoing to identify genes including their gene products and microRNAs that correlate with disease progression and might be used as biomarkers for OS. However, the genomic complexity hampers the identification of reliable biomarkers. Up to now, clinico-pathological factors are the key determinants to guide prognosis and therapeutic treatments. Each day, new studies about OS are published and complicate the acquisition of information to support biomarker discovery and therapeutic improvements. Thus, it is necessary to provide a structured and annotated view on the current OS knowledge that is quick and easily accessible to researchers of the field. Therefore, we developed a publicly available database and Web interface that serves as resource for OS-associated genes and microRNAs. Genes and microRNAs were collected using an automated dictionary-based gene recognition procedure followed by manual review and annotation by experts of the field. In total, 911 genes and 81 microRNAs related to 1331 PubMed abstracts were collected (last update: 29 October 2013). Users can evaluate genes and microRNAs according to their potential prognostic and therapeutic impact, the experimental procedures, the sample types, the biological contexts and microRNA target gene interactions. Additionally, a pathway enrichment analysis of the collected genes highlights different aspects of OS progression. OS requires pathways commonly deregulated in cancer but also features OS-specific alterations like deregulated osteoclast differentiation. To our knowledge, this is the first effort of an OS database containing manual reviewed and annotated up-to-date OS knowledge. It might be a useful resource especially for the bone tumor research community, as specific information about genes or microRNAs is quick and easily accessible. Hence, this platform can support the ongoing OS research and biomarker discovery

H3F3A (Histone 3.3) G34W Immunohistochemistry: A Reliable Marker Defining Benign and Malignant Giant Cell Tumor of Bone

Giant cell tumor of bone (GCTB) is a locally aggressive subarticular tumor. Having recently reported that H3.3 G34W mutations are characteristic of this tumor type, we have now investigated the sensitivity and specificity of the anti-histone H3.3 G34W rabbit monoclonal antibody in a wide variety of tumors including histologic mimics of GCTB to assess its value as a diagnostic marker. We also determined the incidence of H3.3 G34 mutations in primary malignant bone tumors as assessed by genotype and H3.3 G34W immunostaining. A total of 3163 tumors were tested. Totally, 213/235 GCTB (90.6%) showed nuclear H3.3 p.G34W immunoreactivity. This was not the case for the rare variants, p.G34L, M, and V, which occurred most commonly in the small bones of the hands, patella, and the axial skeleton. If these sites were excluded from the analysis, H3.3 G34W expression was found in 97.8% of GCTB. Malignant bone tumors initially classified as osteosarcomas were the only other lesions (n=11) that showed G34W expression. Notably an additional 2 previously reported osteosarcomas with a p.G34R mutation were not immunoreactive for the antibody. A total of 11/13 of these malignant H3.3-mutant tumors exhibited an osteoclast-rich component: when imaging was available all but one presented at a subarticular site. We propose that subarticular primary malignant bone sarcoma with H3.3 mutations represent true malignant GCTB, even in the absence of a benign GCTB component

HOX D13 expression across 79 tumor tissue types.

HOX genes control normal development, primary cellular processes and are characterized by a unique genomic network organization. Locus D HOX genes play an important role in limb generation and mesenchymal condensation. Dysregulated HOXD13 expression has been detected in breast cancer, melanoma, cervical cancer and astrocytomas. We have investigated the epidemiology of HOXD13 expression in human tissues and its potential deregulation in the carcinogenesis of specific tumors. HOXD13 homeoprotein expression has been detected using microarray technology comprising more than 4,000 normal and neoplastic tissue samples including 79 different tumor categories. Validation of HOXD13 expression has been performed, at mRNA level, for selected tumor types. Significant differences are detectable between specific normal tissues and corresponding tumor types with the majority of cancers showing an increase in HOXD13 expression (16.1% normal vs. 57.7% cancers). In contrast, pancreas and stomach tumor subtypes display the opposite trend. Interestingly, detection of the HOXD13 homeoprotein in pancreas-tissue microarrays shows that its negative expression has a significant and adverse effect on the prognosis of patients with pancreatic cancer independent of the T or N stage at the time of diagnosis. Our study provides, for the first time, an overview of a HOX protein expression in a large series of normal and neoplastic tissue types, identifies pancreatic cancer as one of the most affected by the HOXD13 hoemoprotein and underlines the way homeoproteins can be associated to human cancerogenesis

An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing

The last decade has seen the majority of primary bone tumor subtypes become defined by molecular genetic alteration. Examples include giant cell tumour of bone (H3F3A p.G34W), chondroblastoma (H3F3B p.K36M), mesenchymal chondrosarcoma (HEY1‐NCOA2), chondromyxoid fibroma (GRM1 rearrangements), aneurysmal bone cyst (USP6 rearrangements), osteoblastoma/osteoid osteoma (FOS/FOSB rearrangements), and synovial chondromatosis (FN1‐ACVR2A and ACVR2A‐FN1). All such alterations are mutually exclusive. Many of these have been translated into clinical service using immunohistochemistry or FISH. 60% of central chondrosarcoma is characterised by either isocitrate dehydrogenase (IDH) 1 or IDH2 mutations distinguishing them from other cartilaginous tumours. In contrast, recurrent alterations which are clinically helpful have not been found in high grade osteosarcoma. High throughput next generation sequencing has also proved valuable in identifying germ line alterations in a significant proportion of young patients with primary malignant bone tumors. These findings will play an increasing role in reaching a diagnosis and in patient management

The driver landscape of sporadic chordoma.

Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma.Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma

Molekulare Charakterisierung von Osteosarkomen

Zusammenfassung: Osteosarkome sind seltene Knochentumoren mit einer Inzidenz von etwa 5-6 Fällen/1.000.000Einwohner/Jahr. Da sich die Prognose der Erkrankung in den letzten 30Jahren kaum verändert hat und z.Z. immer noch mehr als 30 % der Patienten an der Erkrankung versterben, ist ein besseres Verständnis der molekularen Tumorentstehung zur Identifizierung prognostischer und prädiktiver Biomarker sowie potenzieller therapeutischer Targets dringend notwendig. Mit Hilfe genomweiter SNP-Chip-Analysen konnten wir eine genetische Signatur beschreiben, die eine prognostische Prädiktion bereits an der diagnostischen Biopsie erlaubt. Des Weiteren scheint der MikroRNA-Cluster17-92 bei Osteosarkomen konstitutiv überexprimiert zu sein. Die hier enthaltenen MikroRNAs sind in ein regulatorisches Netzwerk zahlreicher beim Osteosarkom als dereguliert beschriebener Onkogene und Tumorsuppressor-Gene eingeflochten, sodass es sich hier um einen zentralen Regulator bei der Tumorentstehung handeln könnt