Nav: Home

There goes the neighborhood: Changes in chromosome structure activate cancer-causing genes

March 03, 2016

CAMBRIDGE, Mass. (March 3, 2016) - In a finding with enormous implications for cancer diagnostics and therapeutics, Whitehead Institute scientists have discovered that breaches in looping chromosomal structures known as "insulated neighborhoods" can activate oncogenes capable of fueling aggressive tumor growth.

"This new understanding of the role of chromosome structure in cancer gene misregulation reveals the powerful influence of the genome's structure in human health and disease," says Whitehead Member Richard Young, whose lab's research is reported online this week in the journal Science.

Young's most recent findings build on previous work in which the lab charted human genome structure and described its influence on gene control in healthy cells. By mapping the genome's three-dimensional (3D) conformation, researchers found that key genes controlling cell identity are found in insulated neighborhoods, whose loops are maintained through anchor sites bound by the protein CTCF. All essential gene regulation, including control of proper activation and repression, takes place within these enclosed neighborhoods.

The scientists had also found that these CTCF loop anchor sites are maintained across various cell types in the human body and highly conserved in primate genomes, emphasizing their importance in normal development. Such widespread structural conservation led the researchers to hypothesize that disruptions in genome conformation might be associated with disease, including cancer.

Sure enough, subsequent systematic genomic analysis of >50 cancer cell types revealed mutations affecting CTCF anchor sites, leading to the loss of insulated neighborhood boundaries. Such neighborhood breaches were found especially frequently in T-cell acute lymphoblastic leukemia, esophageal and liver carcinoma, and in some cases allowed enhancer elements to contact and activate previously silent oncogenes.

"We hadn't known if these types of mutations contributed to cancer," says Young. "Now we have multiple examples where these disruptions activate oncogenes that play major roles in tumorigenesis."

Researchers in Young's lab note that this oncogenic mechanism is not only widespread in cancer, but may be valuable for identifying the key genes that drive poorly understood cancers.

"In some cancers, such as esophageal carcinoma, the most frequent genetic mutation occurs at the CTCF sites, which is quite striking," says Denes Hnisz, a postdoctoral researcher in the Young lab and co-first author of the Science paper. "In addition, there are still many cancers whose driver mutations and oncogenes are not known and mapping altered structures may reveal the key oncogenes in these cancers."

In a final step confirming the relationship between structural disruption and oncogenesis, Hnisz and co-first author Abe Weintraub, a graduate student in Young's lab, used genome editing techniques to introduce CTCF anchor site deletions in non-malignant cells. These mutations were sufficient to activate oncogenes that are silent in normal cells.

The new findings suggest that future mapping of genome structure in individual patient cancers may improve diagnosis and help guide treatment protocols. "Now that we understand how perturbations in the genome's structure can contribute to oncogenesis, we're developing strategies to efficiently diagnose and potentially fix these faulty neighborhoods," says Weintraub.
-end-
This work was supported by the National Institutes of Health (grants HG002668, CA109901, HG003143, NS088538, MH104610, and AI120766), an Erwin Schrödinger Fellowship from the Austrian Science Fund, Ludwig Graduate Fellowship funds, the Laurie Kraus Lacob Faculty Scholar Award in Pediatric Translational Research, Hyundai Hope on Wheels, an Individual Postdoctoral grant, and a Sapere Aude Research Talent grant from the Danish Council for Independent Research, Medical Sciences.

Richard Young's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.

Full Citation:

"Activation of proto-oncogenes by disruption of chromosome neighborhoods"

Science, online March 3, 2016

Denes Hnisz (1), Abraham S. Weintraub (1,2), Daniel S. Day (1), Anne-Laure Valton (3), Rasmus O. Bak (4), Charles H. Li (1,2), Johanna Goldmann (1), Bryan R. Lajoie (3), Zi Peng Fan (1,5), Alla A. Sigova (1), Jessica Reddy (1,2), Diego Borges-Rivera (1,2), Tong Ihn Lee (1), Rudolf Jaenisch (1,2), Matthew H. Porteus (4), Job Dekker (3,6), Richard A. Young (1,2)

1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA

2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

3. Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605-0103, USA

4. Department of Pediatrics, Stanford University, Stanford, California, USA

5. Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

6. Howard Hughes Medical Institute

Whitehead Institute for Biomedical Research

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Setbacks
Failure can feel lonely and final. But can we learn from failure, even reframe it, to feel more like a temporary setback? This hour, TED speakers on changing a crushing defeat into a stepping stone. Guests include entrepreneur Leticia Gasca, psychology professor Alison Ledgerwood, astronomer Phil Plait, former professional athlete Charly Haversat, and UPS training manager Jon Bowers.
Now Playing: Science for the People

#524 The Human Network
What does a network of humans look like and how does it work? How does information spread? How do decisions and opinions spread? What gets distorted as it moves through the network and why? This week we dig into the ins and outs of human networks with Matthew Jackson, Professor of Economics at Stanford University and author of the book "The Human Network: How Your Social Position Determines Your Power, Beliefs, and Behaviours".