‘Master’ Gene Tied to Deadlier Cancer Types
Like rival explorers planting flags in the same uncharted territory, two competing scientific teams have discovered a “master” gene that, when defective, makes some cancers especially deadly, including those of the brain, prostate, breast and endometrium.
The discovery is “extremely exciting,” because it shows that the same basic genetic process worsens a variety of fairly common cancers, said Dr. Richard Kaplan, director of brain tumor treatment trials at the National Cancer Institute. The finding may improve cancer treatment by identifying aggressive cancers or leading to new drugs that mimic the gene’s anti-tumor action, the researchers say.
The gene is of a type known as a tumor suppressor, so called because it slows the growth or spread of tumors. If the normal version of the gene acquires a mutation, or disappears entirely from the chromosome, the gene’s braking function is lost, and the cell that harbors it is turned into a fast-growing, aggressive cancerous tumor.
The researchers say the mutated version of the newly discovered gene plays a role in at least half of the cases of the deadliest brain cancer, glioblastoma multiforme, which kills about 10,000 people a year in the United States. It is also implicated in a substantial number of breast and prostate cancers, they say.
The mutated gene’s link to prostate cancer is “really important,” said Dr. Richard Cote, a pathologist and cancer researcher at the USC School of Medicine. Though the affliction is one of the most commonly diagnosed cancers in the United States, little is known about what causes it or why it is far more aggressive in some cases than in others.
“This may be a steppingstone” to understanding the disease, Cote said of the new gene, adding that the discovery has prompted his lab to study it. “We’re enthusiastic enough about the finding to commit resources to it,” he said.
And according to research made public this week, the mutated gene is also implicated in cancer of the endometrium--the lining of the uterus--which accounts for 13% of all cancers in women. Researchers at Tohoku University in Japan and the University of Maryland report in the journal Nature Genetics that the gene was mutated in about half the 38 endometrial tumors they tested. Coauthor Dr. Stephen Meltzer, a Maryland gastroenterologist, said the gene appeared to function as a “gatekeeper,” allowing some endometrial tumors to get started or grow swiftly.
While scientific teams in New York City and Houston independently discovered the gene at the same time, publishing their results within days of one another earlier this year, the researchers followed very different roads.
Dr. Peter Steck, at the M.D. Anderson Cancer Center in Houston, began analyzing genetic changes in brain tumors more than a decade ago. His lab and others made a crucial observation that researchers have puzzled over for years: In many of the advanced tumors studied, a length of a particular chromosome, No. 10, was missing, somehow deleted in the course of cell division. So began his search for a tumor-suppressor gene in the DNA of that chromosome.
Steck gradually narrowed the search for the suspect gene, one of the 4,000 that typically make up a human chromosome. Last year, he joined forces with the Salt Lake City biotech firm Myriad Genetics, whose massive gene-sequencing computers identified a candidate gene within months, which researchers call MMAC1.
They tested the finding by surgically implanting two sets of brain-tumor cells in lab mice. While cells that lacked the gene blossomed into a tumor, those still endowed with it did not flourish. “Taking that approach,” Steck said, “we knew approximately what the gene should do.”
Meanwhile, at Columbia University’s College of Physicians and Surgeons, molecular biologist Roman Parsons and co-workers were homing in on the same patch of DNA. Using a genetic technique called representational difference analysis, developed by co-workers at the Cold Spring Harbor Laboratory on Long Island, they found that the DNA in a number of breast cancer cells differed from DNA in healthy breast cells.
They traced a key difference to a gene on chromosome No. 10 that they called P-TEN. And like the Houston group, they found that the gene was altered in other cancers too.
What sets this gene discovery apart from others, which have become so frequent that even experts joke about the “gene of the week,” is that the researchers have a clear idea of what the gene actually does. Sean Tavtigian, a molecular biologist at Myriad, which is collaborating with Steck, said the enzyme controlled by the gene appeared to help a cell communicate with surrounding tissues; lacking the enzyme, the cell’s ability to sense neighboring cells goes haywire, prompting it to multiply and invade the tissues.
Normally, he said, “the proximity of another cell generates a signal saying, ‘Don’t divide or crawl past me.’ That signal is not getting transmitted” in cells with a mutated form of the gene; as a result, he said, such cells may also be more inclined to break loose from a sprouting tumor and metastasize, or spread to other tissues.
The discovery might help medical researchers develop new tools for identifying the deadliest of tumors--information that could affect treatment. A prostate tumor harboring the gene mutation would perhaps best be treated very aggressively, with the gamut of radiation and surgery, said Steck. In contrast, a tumor carrying a normal copy of the gene might be more benign, calling for more conservative treatment, such as limited surgery without radiation.
Another possible practical benefit, though also some years in the future, would be drugs or even synthetic genes specifically designed to compensate for the mutated gene, Tavtigian said.
Given the scientific novelty and therapeutic potential of the discovery, the New York and Texas groups competed intensely to win the race into print. The New York group won by a nose--it submitted its paper to the journal Science two weeks sooner than it had planned, after hearing that the Texas group was hot on the trail. Both groups have also applied for patents on the discovery, but settling that dispute may take years.
Columbia’s Parsons chalked it up to “normal scientific competition.” And while one group may ultimately lose the rights to commercialize the finding, he said, the public benefits from the simultaneous discovery because people can be reassured that it is real and “not just a fluke.”
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When a Gene Goes Bad
A newly discovered master gene, called MMAC1 or P-TEN, may be behind some fast-growing tumors. When mutated, the so-called tumor suppressor gene disrupts the cellular signaling that retards the growth of cancer cells.
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Normal Cell Communications
A healthy cell typically communicates with its neighbors by emitting protein factors that inhibit their growth. A cell receiving the signal at its surface receptor relays it to the nucleus, where the tumor suppressor gene imbedded in DNA triggers the release of substances that prevent or slow cell division.
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A malignant Tumor
A microsopic section of a low-grade brain tumor,left, contains far fewer cancer cells than a section of the aggressive tumor, right, a glioblastoma multiforme cancer that harbored the mutated tumor suppressor gene.
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Mutated Gene’s Effect
When the gene is disrupted, however, the growth-blocking system goes haywire, and cells can grow aggressively, perhaps invading surrounding tissue.
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The “brakes” on cell division are lost, and cell becomes fast-growing tumor.
Researched by TERENCE MONMANEY / Los Angeles Times
