Featured Research

from universities, journals, and other organizations

Cancer genes hijack enhancers

June 23, 2014
German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
Unlike most other forms of cancer, medulloblastomas exhibits very few mutations in growth-promoting genes. Scientists have now made an important discovery about a particularly malignant subgroup of medulloblastomas: often the cancer-causing genes are transcribed at higher or lower levels than normal. This change is due to regulatory mechanisms that were previously unknown. For example, one cancer-gene hijacks a so-called 'enhancer.'

Medulloblastoma is the most common childhood brain tumor. It is classified in four distinct subgroups that vary strongly in terns of the aggressiveness of the disease. Group 3 and Group 4 tumors, which are very challenging, are particularly common. "For these two tumor groups, hardly any characteristic genomic changes that drive tumor growth and would make potential targets for drug development have been identified," says Prof. Dr. Peter Lichter from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), who is coordinator of the PedBrain Tumor network. The PedBrain network is part of the International Cancer Genome Consortium (ICGC), whose researchers are systematically analyzing all genomic alterations in pediatric brain cancer to discover new targets for the development of gentler modes of treatment.

Related Articles

Dr. Paul Northcott and coworkers from the first team took a closer look at 137 cases of the more aggressive Group 3 and Group 4 medulloblastomas. They discovered a phenomenon that had never been observed before in brain cancer. In many of the tumor genomes, large regions of DNA had been deleted or duplicated or had changed their orientation. Despite their different nature, these structural changes had identical consequences in all tumors under investigation: One of two oncogenes called GFI1 and GFI1B, which are not active in healthy brain tissue, is transcribed in these tumors and thus contributes to the development of cancer.

The PedBrain researchers also discovered what causes this strange phenomenon. Various structural changes had moved the oncogene from a usually inactive environment to a position close to DNA sequences called "enhancers," which are involved in the activation of genes. In mice, the researchers subsequently proved that activated GFI1B leads to the development of brain cancer, providing evidence that the "hijacked" gene enhancers promote the onset of cancer.

"It is quite possible that hijacked enhancers also play a role as activating mechanisms in many other types of cancer," says Prof. Dr. Stefan Pfister, a molecular geneticist at the DKFZ, who also works as a pediatrician at Heidelberg University Hospital. "However, one can only discover them through a very careful analysis of the genome, and therefore they are easily missed."

The researchers are particularly pleased that their work may directly contribute to the development of better treatments for children with brain cancer. Substances that block the effects of the GFI1 and GFI1B oncogenes are already being tested in clinical trials and might now also be used to slow down the growth of aggressive Group 3 and Group 4 medulloblastomas.

The second team focused their investigations on the so-called "epigenetic" regulation of gene activity by chemical labels in DNA. The researchers compared patterns of DNA methylation across the whole genome from 42 medulloblastomas with the patterns found in healthy control tissue.

The number of methylation groups found in the promoter region, i.e., the region of DNA that stimulates the transcription of a gene, has been considered a crucial factor in gene activity. For the first time, Volker Hovestadt and his colleagues have discovered that altered methyl groups within genes also are also relevant to their activation. Numerous genes in tumor cells exhibited low levels of methylation compared to healthy counterparts. At the same time, they were transcribed significantly more frequently than in healthy cells. This is clear evidence that a lack of methyl groups has functional effects.

"The regulation of gene activity by methyl labels within a particular gene has never been observed, at least not to such a marked extent," Lichter says. "In some of the tumors we found nearly 1000 genes that were methylated at lower levels than their counterparts in healthy cells."

PedBrain network coordinator Lichter summarized the relevance of the two Nature publications: "The results show the major relevance of the epigenetic regulation of genes, including known oncogenes, in medulloblastoma. In addition, we have identified GFl1 and GFl1B as an Achilles' heel of the most dangerous types of medulloblastoma. For the first time, this reveals a molecular weak spot in these tumors that can be targeted in drug development."

Story Source:

The above story is based on materials provided by German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). Note: Materials may be edited for content and length.

Journal References:

  1. Volker Hovestadt, David T. W. Jones, Simone Picelli, Wei Wang, Marcel Kool, Paul A. Northcott, Marc Sultan, Katharina Stachurski, Marina Ryzhova, Hans-Jörg Warnatz, Meryem Ralser, Sonja Brun, Jens Bunt, Natalie Jäger, Kortine Kleinheinz, Serap Erkek, Ursula D. Weber, Cynthia C. Bartholomae, Christof von Kalle, Chris Lawerenz, Jürgen Eils, Jan Koster, Rogier Versteeg, Till Milde, Olaf Witt, Sabine Schmidt, Stephan Wolf, Torsten Pietsch, Stefan Rutkowski, Wolfram Scheurlen, Michael D. Taylor, Benedikt Brors, Jörg Felsberg, Guido Reifenberger, Arndt Borkhardt, Hans Lehrach, Robert J. Wechsler-Reya, Roland Eils, Marie-Laure Yaspo, Pablo Landgraf, Andrey Korshunov, Marc Zapatka, Bernhard Radlwimmer, Stefan M. Pfister, Peter Lichter. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature, 2014; 510 (7506): 537 DOI: 10.1038/nature13268
  2. Paul A. Northcott, Catherine Lee, Thomas Zichner, Adrian M. Stütz, Serap Erkek, Daisuke Kawauchi, David J. H. Shih, Volker Hovestadt, Marc Zapatka, Dominik Sturm, David T. W. Jones, Marcel Kool, Marc Remke, Florence M. G. Cavalli, Scott Zuyderduyn, Gary D. Bader, Scott VandenBerg, Lourdes Adriana Esparza, Marina Ryzhova, Wei Wang, Andrea Wittmann, Sebastian Stark, Laura Sieber, Huriye Seker-Cin, Linda Linke, Fabian Kratochwil, Natalie Jäger, Ivo Buchhalter, Charles D. Imbusch, Gideon Zipprich, Benjamin Raeder, Sabine Schmidt, Nicolle Diessl, Stephan Wolf, Stefan Wiemann, Benedikt Brors, Chris Lawerenz, Jürgen Eils, Hans-Jörg Warnatz, Thomas Risch, Marie-Laure Yaspo, Ursula D. Weber, Cynthia C. Bartholomae, Christof von Kalle, Eszter Turányi, Peter Hauser, Emma Sanden, Anna Darabi, Peter Siesjö, Jaroslav Sterba, Karel Zitterbart, David Sumerauer, Peter van Sluis, Rogier Versteeg, Richard Volckmann, Jan Koster, Martin U. Schuhmann, Martin Ebinger, H. Leighton Grimes, Giles W. Robinson, Amar Gajjar, Martin Mynarek, Katja von Hoff, Stefan Rutkowski, Torsten Pietsch, Wolfram Scheurlen, Jörg Felsberg, Guido Reifenberger, Andreas E. Kulozik, Andreas von Deimling, Olaf Witt, Roland Eils, Richard J. Gilbertson, Andrey Korshunov, Michael D. Taylor, Peter Lichter, Jan O. Korbel, Robert J. Wechsler-Reya, Stefan M. Pfister. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature, 2014; DOI: 10.1038/nature13379

Cite This Page:

German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). "Cancer genes hijack enhancers." ScienceDaily. ScienceDaily, 23 June 2014. <www.sciencedaily.com/releases/2014/06/140623120312.htm>.
German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). (2014, June 23). Cancer genes hijack enhancers. ScienceDaily. Retrieved March 4, 2015 from www.sciencedaily.com/releases/2014/06/140623120312.htm
German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). "Cancer genes hijack enhancers." ScienceDaily. www.sciencedaily.com/releases/2014/06/140623120312.htm (accessed March 4, 2015).

Share This

More From ScienceDaily

More Health & Medicine News

Wednesday, March 4, 2015

Featured Research

from universities, journals, and other organizations

Featured Videos

from AP, Reuters, AFP, and other news services

Mom Triumphs Over Tragedy, Helps Other Families

Mom Triumphs Over Tragedy, Helps Other Families

AP (Mar. 3, 2015) — After her son, Dax, died from a rare form of leukemia, Julie Locke decided to give back to the doctors at St. Jude Children&apos;s Research Hospital who tried to save his life. She raised $1.6M to help other patients and their families. (March 3) Video provided by AP
Powered by NewsLook.com
Looted and Leaking, South Sudan's Oil Wells Pose Health Risk

Looted and Leaking, South Sudan's Oil Wells Pose Health Risk

AFP (Mar. 3, 2015) — Thick black puddles and a looted, leaking ruin are all that remain of the Thar Jath oil treatment facility, once a crucial part of South Sudan&apos;s mainstay industry. Duration: 01:13 Video provided by AFP
Powered by NewsLook.com
Woman Convicted of Poisoning Son

Woman Convicted of Poisoning Son

AP (Mar. 3, 2015) — A woman who blogged for years about her son&apos;s constant health woes was convicted Monday of poisoning him to death by force-feeding heavy concentrations of sodium through his stomach tube. (March 3) Video provided by AP
Powered by NewsLook.com
Treadmill Test Can Predict Chance Of Death Within A Decade

Treadmill Test Can Predict Chance Of Death Within A Decade

Newsy (Mar. 2, 2015) — Johns Hopkins researchers analyzed 58,000 heart stress tests to come up with a formula that predicts a person&apos;s chances of dying in the next decade. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.


Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News


Free Subscriptions

Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile

Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?

Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins