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Ludwig Harvard study reveals how non-mutational changes to the genome drive a type of cancer

OCTOBER 16, 2019, NEW YORK— Most gastrointestinal stromal tumors (GISTs), a type of soft-tissue cancer (sarcoma), are caused by mutations in genes that can be effectively targeted with drugs that inhibit the activity of rogue cancer-promoting enzymes.

But an estimated 10% to 20% of GISTs have no identifiable or targetable mutations. Now researchers led by Ludwig Harvard Co-director George Demetri and Ludwig Harvard investigator Bradley Bernstein—along with colleagues at the Broad Institute of MIT and Harvard, and Massachusetts General Hospital (MGH)—have identified mechanisms that give rise to these cancers and shown, in preclinical studies, how they might be treated.

 Their findings, which appear in the current issue of Nature, reveal how “epigenetic” changes—alterations in how genes are read that stem from the remodeling of DNA and its protein packaging, or chromatin—generate GISTs and other cancers. They also show how the effects of those changes might be disrupted to treat such GISTs.

“Your genome consists of about six feet of DNA wrapped very carefully to fit into microscopic cells. One of the tricks that the cell uses to compact all of this DNA is to tie it up into little loops,” says Bernstein, who is also a professor of pathology at MGH and a member of the Broad Institute.

Each loop, Bernstein explains, is separated by a knot, known as an “insulator.” The researchers found that one such insulator normally keeps a cancer-causing gene, FGF4, from coming into contact with a stretch of DNA that serves as a switch to turn on an unrelated gene. In normal cells, the cancer-causing gene and the switch are in separate loops and sequestered from one another. However, in some forms of GIST, the insulator is disrupted and the loops merge into one, which causes the on-switch to abnormally activate the cancer-causing FGF4 gene.

The researchers showed how a separate epigenetic abnormality dismantles insulators in these tumors, causing the aberrant contacts between on-switches and oncogenes. In addition to the disrupted insulator that activated the FGF4 oncogene, they identified a second disrupted insulator near a normal gene called KIT—the gene that is activated by mutations in most other GISTs.

The team validated their mechanistic findings in a mouse model. They also showed that the GISTs in these mice could be suppressed with a class of drugs known as fibroblast growth factor receptor inhibitors, either alone or in combination with a targeted therapy called sunitinib, a drug that is used to treat GISTs.

 “The insights from our collaborative research can open new avenues for testing combinations of new therapies in this subset of GIST and other cancers,” said Demetri, who is also a professor at Harvard Medical School and an associate director for clinical sciences at the Dana-Farber Cancer Institute/Harvard Cancer Center.

More detail about these findings is available in the MGH release from which this summary is derived.


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