vom 12/16/2016

Kidnapped enhancer activates cancer gene

The DNA of cancer cells is different from healthy cells. Often, genes or entire gene regions are deleted or duplicated. Due to such structural mutations, cancer-releasing genes can enter the vicinity of genetic enhancers and cause tumor growth. Heidelberg scientists have now shown, through large-scale analysis of different tumors, that "enhancer kidnapping" is frequently found in cancer. The researchers of the National Center for Tumor Diseases (NCT) Heidelberg and the European Molecular Biology Laboratory (EMBL) in Heidelberg discovered that the gene IGF2 is also activated by this mechanism. The scientists have now published their results in Nature Genetics.

The NCT Heidelberg is a joint institution of the German Cancer Research Center (DKFZ), the Heidelberg University Hospital and German Cancer Aid (Deutsche Krebshilfe).

Duplications of different-sized sections of DNA are often found in the genome. How this affects the organism has only been partially investigated. Depending on their location in the genome, such duplications can form new functional units, the so-called "topologically associated domains" (TAD). These are DNA loops, which on average are one million base pairs long and contain one or more genes and their control elements. They control when and in which cells a gene is switched on or off.

Using a specially developed medical informatics method, the researchers systematically investigated the occurrence of gene duplications and the phenomenon of "enhancer kidnapping" on 7,416 previously published cancer genes. They found that hijacking of foreign enhancer elements by carcinogenic genes is a common process in solid tumors, and have now shown this process for the first time in colorectal cancer and lung cancer. The scientists from the NCT Heidelberg, EMBL and the German Cancer Research Center (DKFZ) took a closer look at a well-known marker for particularly aggressive and chemotherapy-resistant cancer forms, the IGF2 gene (insulin-like growth factor 2). "We noticed that IGF2 was over 250 times more active in approximately 6 to 7 percent of colorectal cancer patients than in healthy control cells. And this, although the gene was not significantly more common in their DNA", reports Professor Hanno Glimm, physician and scientist at the NCT, DKFZ and the German Cancer Consortium (DKTK). The scientists discovered in the analysis of the three-dimensional structure of the genome, why this genetic information was present so often: within one genetic region, IGF2 had doubled. This tandem structure created a new loop that brought IGF2 close to a whole group of enhancers, also known as the "super-enhancer". The new constellation activated the IGF2 gene to a far greater extent than usual. The research results help to better understand cancer-inducing mechanisms, and can contribute to the development of more targeted therapies against tumors where these investigated changes play a role.

Nature Genetics has published the results of the study. The two corresponding authors are Hanno Glimm of the NCT Heidelberg and Jan O. Korbel of EMBL Heidelberg. As an NCT 3.0. Project, this work was funded by the DFG, the Baden-Württemberg Foundation, the Helmholtz Initiative iMed, and German Cancer Aid.

Weischenfeldt J et al. (2016) Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking. Nature Genetics DOI: 10.1038/ng.3722

The following image for the press release is available for download free of charge:
The gene IGF2 (green) is duplicated in the DNA strand (duplicated region: orange). This results in a new three-dimensional structure that brings the cancer gene close to the enhancer elements (purple).

Usage of image material for press releases
The use of this image is free of charge. The NCT Heidelberg permits one-time use in connection with the reporting on the topic of the press release. The following must be provided as picture credits: "Source: Hanno Glimm / Jan Korbel".

Press contact:
Dr. Friederike Fellenberg
Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg
Presse- und Öffentlichkeitsarbeit
Im Neuenheimer Feld 460
69120 Heidelberg
Tel.: +49 6221 56-5930
Fax: +49 6221 56-5350
E-Mail: friederike.fellenberg@nct-heidelberg.de

Dr. Alexandra Moosmann
Presse- und Öffentlichkeitsarbeit
Deutsches Konsortium für Translationale Krebsforschung Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 1662
Email: a.moosmann@dkfz-heidelberg.de

Dr. Stefanie Seltmann
Deutsches Krebsforschungszentrum (DKFZ)
Presse- und Öffentlichkeitsarbeit
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
69120 Heidelberg
Tel.: +49 6221 42-2854
Fax: +49 6221 42-2968
E-Mail: S.Seltmann@dkfz.de

Doris Rübsam-Brodkorb
Universitätsklinikum Heidelberg und Medizinische Fakultät der Universität Heidelberg
Presse- und Öffentlichkeitsarbeit
Im Neuenheimer Feld 672
69120 Heidelberg
Tel.: +49 6221 56-5052
Fax: +49 6221 56-4544
E-Mail: doris.ruebsam-brodkorb@med.uni-heidelberg.de

The National Center for Tumor Diseases (NCT) Heidelberg
The National Center for Tumor Diseases (NCT) Heidelberg is a joint institution of the German Cancer Research Center, Heidelberg University Hospital and German Cancer Aid. The NCT's goal is to link promising approaches from cancer research with patient care from diagnosis to treatment, aftercare and prevention. The interdisciplinary tumor outpatient clinic is the central element of the NCT. Here the patients benefit from an individual treatment plan prepared in a timely manner in interdisciplinary expert rounds, the so-called tumor boards. Participation in clinical studies provides access to innovative therapies. The NCT thereby acts as a pioneering platform that translates novel research results from the laboratory into clinical practice. The NCT cooperates with self-help groups and supports them in their work. Since 2015, a second site for the NCT beside Heidelberg has been under development in Dresden.

German Cancer Consortium (DKTK)
The German Cancer Consortium (DKTK) is a joint long-term initiative involving the German Federal Ministry of Education and Research (BMBF), participating German states and the German Cancer Research Center (DKFZ) and was established as one of six German Health Research Centres (DZGs).
As DKTK’s core center the DKFZ works together with research institutions and hospitals in Berlin, Dresden, Essen/Düsseldorf, Frankfurt/Mainz, Freiburg, Munich, Heidelberg and Tübingen to create the best possible conditions for clinically oriented cancer research. The consortium promotes interdisciplinary research at the interface between basic research and clinical research, as well as clinical trials for innovative treatments and diagnostic methods. Another key focus of the consortium’s work is on developing research platforms to speed up the application of personalized cancer treatments and to improve the diagnosis and prevention of cancer.

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
The German Cancer Research Center (DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.

Heidelberg University Hospital and Medical Faculty Heidelberg
Health care, research and teaching of international standing
Heidelberg University Hospital is one of the most important medical centers in Germany; Heidelberg University's Medical Faculty is one of Europe's most prestigious biomedical research facilities. Their shared objective is the development of innovative diagnostics and treatments and their prompt implementation for the benefit of the patient. The hospital and faculty employ approximately 12 600 individuals and are involved in training and qualification. Every year approximately 66 000 patients are treated as inpatients or day patients in more than 50 specialized clinical departments with about 1 900 beds, with more than 1 million patients being treated as outpatients. The Heidelberg Curriculum Medicinale (HeiCuMed) is at the forefront of medical training in Germany. At present approx. 3500 prospective physicians are studying in Heidelberg.

European Molecular Biology Laboratory (EMBL)
The European Molecular Biology Laboratory is a basic research institute funded by public research monies from 20 member states. Research at EMBL is conducted by approximately 80 independent groups covering the spectrum of molecular biology. The Laboratory has five units: the main Laboratory in Heidelberg, and outstations in Hinxton (the European Bioinformatics Institute), Grenoble, Hamburg, and Monterotondo near Rome. The cornerstones of EMBL’s mission are: to perform basic research in molecular biology; to train scientists, students and visitors at all levels; to offer vital services to scientists in the member states; to develop new instruments and methods in the life sciences and to actively engage in technology transfer activities.