Genome reorganization in different cancer types: detection of cancer specific breakpoint regions

Background: Tumorigenesis is a multi-step process which is accompanied by substantial changes in genome organization. The development of these changes is not only a random process, but rather comprise specific DNA regions that are prone to the reorganization process. Results: We have analyzed previously published SNP arrays from three different cancer types (pancreatic adenocarcinoma, breast cancer and metastatic melanoma) and from non-malignant control samples. We calculated segmental copy number variations as well as breakpoint regions. Some of these regions were not randomly involved in genome reorganization since we detected fifteen of them in at least 20% of all tumor samples and one region on chromosome 9 where 43% of tumors have a breakpoint. Further, the top-15 breakpoint regions show an association to known fragile sites. The relevance of these common breakpoint regions was further confirmed by analyzing SNP arrays from 917 cancer cell lines. Conclusion: Our analyses suggest that genome reorganization is common in tumorigenesis and that some breakpoint regions can be found across all cancer types, while others exclusively occur in specific entities

Einfluss von Kopienzahlvariationen auf die Tumorentwicklung

Tumorentstehung ist ein Prozess, bei dem die Abläufe innerhalb der Zelle schrittweise verändert werden. Die vielfältigen Interaktionen bei der Tumorentstehung sind jedoch bislang nicht vollständig erforscht. Bisher wurden vorwiegend Genexpressionsanalysen genutzt, die jedoch nur eine Zeitaufnahme aller Genexpressionen innerhalb der Zelle darstellen und somit allein nicht ausreichend zur Charakterisierung eines Tumors. Wir haben mithilfe von Affymetrix Mouse Diversity Genotyping Microarrays Mausbrustdrüsengewebe entsprechend unserem Dreistufen-Mausmodell analysiert und die Kopienzahländerungen berechnet. Wir fanden eine zunehmende stufenweise Änderung von den transgenen zu den Tumorproben. Die Berechnung von chromosomalen Segmenten mit gleicher Kopienzahl zeigte deutliche Fragmentmuster. Unsere Analysen zeigen, dass die Tumorentstehung ein schrittweiser Prozess ist, der sowohl durch Amplifikationen als auch Deletionen chromosomaler Abschnitte definiert ist. Wir fanden charakteristisch konservierte Fragmentierungsmuster und individuelle Unterschiede welche zur Tumorgenese beitragen

SNP microarray analyses reveal copy number alterations and progressive genome reorganization during tumor development in SVT/t driven mice breast cancer

BACKGROUND: Tumor development is known to be a stepwise process involving dynamic changes that affect cellular integrity and cellular behavior. This complex interaction between genomic organization and gene, as well as protein expression is not yet fully understood. Tumor characterization by gene expression analyses is not sufficient, since expression levels are only available as a snapshot of the cell status. So far, research has mainly focused on gene expression profiling or alterations in oncogenes, even though DNA microarray platforms would allow for high-throughput analyses of copy number alterations (CNAs). METHODS: We analyzed DNA from mouse mammary gland epithelial cells using the Affymetrix Mouse Diversity Genotyping array (MOUSEDIVm520650) and calculated the CNAs. Segmental copy number alterations were computed based on the probeset CNAs using the circular binary segmentation algorithm. Motif search was performed in breakpoint regions (inter-segment regions) with the MEME suite to identify common motif sequences. RESULTS: Here we present a four stage mouse model addressing copy number alterations in tumorigenesis. No considerable changes in CNA were identified for non-transgenic mice, but a stepwise increase in CNA was found during tumor development. The segmental copy number alteration revealed informative chromosomal fragmentation patterns. In inter-segment regions (hypothetical breakpoint sides) unique motifs were found. CONCLUSIONS: Our analyses suggest genome reorganization as a stepwise process that involves amplifications and deletions of chromosomal regions. We conclude from distinctive fragmentation patterns that conserved as well as individual breakpoints exist which promote tumorigenesis

Der Nacktmull als ein Modellorganismus für Krebsresistenz - Bioinformatische Analysen

Bei Nacktmullen wurde bisher Tumorentstehung nicht beobachtet. Zur Untersuchung der molekularen Ursachen dient der Nacktmull daher als ein wertvoller Modellorganismus für Krebsresistenz. Ziel dieser Arbeit war eine weiterführende Analyse des kürzlich publizierten Genoms des Nacktmulls. Eine Genvorhersage konnte auf Grundlage der vorhandenden Genom- und Transkriptomdaten durchgeführt und ein hypothetisches Netzwerk der Interaktionen der tumorinduzierenden Faktoren erstellt werden. Dieses Netzwerk basiert auf den Tumorsuppressor-Regulationswegen p53 und RB im Menschen. Die Genom- und Transkriptom-Daten des Nacktmulls weisen deutliche Unterschiede zu den Befunden im Menschen auf. Dieser Befund könnte ein erster Anhaltspunkt für die Aufklärung der molekularen Ursachen der Krebsresistenz von Nacktmullen sein

Laser Multi-Pass Narrow-Gap Welding – A Promising Technology for Joining Thick-Walled Components of Future Power Plants

Today, the average worldwide efficiency of coal-fired power plants stands at about 33 percent. The consistent use of state of the art technologies would enable an increase of the average efficiency of up to 47 percent and thus a sharp reduction of greenhouse gas emissions. The importance of improvements in this field becomes apparent when reviewing e.g. plans in Europe in 2017 for new power plants to be built across the continent. About 44 percent of the envisaged 153 gigawatts are still to be generated by fossil-fuel power plants [1]. One technical solution is to increase the steam turbine inlet temperature to 700°C. This, however, requires the use of nickel-based superalloys. Only these alloys satisfy all the requirements with regard to high-temperature, corrosion and oxidation resistance and creep behavior [2], [3]. Due to their relatively poor machinability, forgeability and high material costs compared to the steel-based alloys they are to replace, a more effective welding technology is needed to overcome the disadvantages of conventional welding technologies, i.e. large quantities of filler metal required and high energy input per unit length resulting in distortion and the potential reduction of high-temperature properties

Laser beam welding of atmosphere aluminium die cast material using high frequency beam oscillation and brilliant beam sources

In serial production of components for automotive applications such as cooling and air-conditioning systems, aluminium die-cast material is frequently used due to its excellent castability. The aim of providing light weight components can be approached with thin walled cross sections even for complex structural parts. However, cast components are usually joined to semi-finished products, such as profiles or tubes. The joints are mostly required to be pressure tight. The joining technique for those applications has to be highly productive to obtain high component outcome as well as cost-efficient. Laser beam welding techniques are especially suitable for those tasks. Die-cast components have limited or no weldability due to their manufacturing process. Reasons for that are entrapped gases within pores or cavities under high pressure conditions. Furthermore, the mold release agents for the die-cast process are inappropriate for obtaining homogeneous and sound weld seams. Consequently, a high amount of pores in the weld seam and stochastic melt pool blow-outs occur, which prohibit mostly the use of the component. To solve these issues a new welding technique, remoweld®T, has been developed at Fraunhofer IWS. The unique method has been extensively tested and transferred to serial-production. The decisive step was to use laser sources with brilliant beam quality in combination with a high frequency beam oscillation within the melt pool. In this paper the technological approach will be presented. With the remoweld®T method it was possible to obtain homogeneous weld seams with low porosity and a strongly reduced distortion for the first time. Minor component tolerances and a reproducible joining technique with a high output for serial production can be achieved

Cocos: Constructing multi-domain protein phylogenies

Phylogenies of multi-domain proteins have to incorporate macro-evolutionary events, which dramatically increases the complexity of their construction

Laser Multi-Pass Narrow-Gap Welding – A Promising Technology for Joining Thick-Walled Components of Future Power Plants

Today, the average worldwide efficiency of coal-fired power plants stands at about 33 percent. The consistent use of state of the art technologies would enable an increase of the average efficiency of up to 47 percent and thus a sharp reduction of greenhouse gas emissions. The importance of improvements in this field becomes apparent when reviewing e.g. plans in Europe in 2017 for new power plants to be built across the continent. About 44 percent of the envisaged 153 gigawatts are still to be generated by fossil-fuel power plants [1]. One technical solution is to increase the steam turbine inlet temperature to 700°C. This, however, requires the use of nickel-based superalloys. Only these alloys satisfy all the requirements with regard to high-temperature, corrosion and oxidation resistance and creep behavior [2], [3]. Due to their relatively poor machinability, forgeability and high material costs compared to the steel-based alloys they are to replace, a more effective welding technology is needed to overcome the disadvantages of conventional welding technologies, i.e. large quantities of filler metal required and high energy input per unit length resulting in distortion and the potential reduction of high-temperature properties