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DNA Misfolding Revealed as Novel Oncogenic Mechanism

, by Amy E Blum, M.A. and NCI Staff

The genes PDGFRA and FIP1L1 are normally confined to separate loop domains (A) and rarely interact, but they can become closely associated (B) in tumors with IDH mutations.

Credit: Broad Communications / Lauren Solomon

Researchers studying brain tumors have identified a previously unknown genetic mechanism that may contribute to cancer. Their findings suggest that a change in how DNA is arranged, or packaged, in the cell nucleus may inappropriately activate a gene associated with brain cancer.

Bradley Bernstein, M.D., Ph.D., of the Broad Institute in Cambridge, MA, and his colleagues published their findings December 23 in Nature. The study focused on brain tumors known as gliomas and included lower-grade gliomas, which frequently have mutations in isocitrate dehydrogenase (IDH) genes.

IDH gene mutations in gliomas disrupt the function of IDH, an enzyme participant in the citric-acid cycle. This causes an altered metabolite to prevent the removal of chemical “tags” known as methyl groups from DNA. The new findings suggest that this process, called hypermethylation, may disrupt the packaging of DNA in the cell nucleus and lead to the activation of growth-promoting genes.

Removing Genetic Barriers

The human genome would measure about 6 feet in length if it were stretched out end to end. Cells physically arrange DNA around groups of proteins—together known as chromatin—in the nucleus by forming thousands of loop-like structures. In gliomas with IDH mutations, however, the researchers found that some loops are misfolded, bringing otherwise unrelated areas of the genome together and linking their activity.

The structure of chromatin is “exceptionally intricate,” wrote Matthew R. Grimmer, Ph.D., and Joseph F. Costello, Ph.D., of the University of California, San Francisco, in an accompanying editorial. DNA segments known as insulators normally act as barriers, ensuring that genes and genetic elements in one loop do not interact with counterparts in other loops. But when insulators are altered or missing, which can occur through hypermethylation, the result may be inappropriately linked gene activity, as was observed in IDH-mutant gliomas.

One misfolded loop, in particular, brought into close proximity two genes that usually reside far apart in the genome and rarely interact—a regulatory gene called FIP1L1 and a growth-promoting gene called PDGFRA, which has been linked to the development of gliomas.

When these genes come in close contact, a regulatory region of the FIP1L1 gene continually activates the PDGFRA gene, causing it to spur cell growth, according to the researchers. They used genomic data from projects such as The Cancer Genome Atlas (TCGA) to identify pairs of genes—including these two—that were abnormally expressed in gliomas with IDH mutations.

Turning Normal Genes into Oncogenes

Although FIP1L1 and PDGFRA may cooperate in causing cancer in IDH-mutant gliomas, neither gene has any mutations or alterations, observed coauthor William Flavahan, Ph.D., of the Broad Institute. “Our findings show that defects in chromatin structure can cause the activation of cancer-causing genes that are genetically intact,” he added.

More research is needed to explore the complex mechanism revealed by the study. For instance, are there other genes that promote cancer because of the structural changes induced by IDH1 mutations? Could this mechanism be widespread across cancer types?

“This study has uncovered a new process of cancer development that completes the prevailing paradigm” commented Jean-Claude Zenklusen, Ph.D., of NCI’s Center for Cancer Genomics and the director of TCGA. “The use of multiple modalities of cancer genomics data to discover this mechanism speaks to the rigor of cross-platform, integrated genomic analysis and the power of cancer genomic research to reveal new insights into cancer biology.”

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