Science News - September 24, 2011

Power of the blueprint A recent genetic study identified a segment of chromosome 15 that had relocated to chromosome 17 in a patient with a difficult-to-diagnose case of leukemia. The change, which affected the cancer-related RARA gene (bright blue), was not visible via a microscope.

Chromosome 15

Before deletion After deletion

Chromosome 17

Before insertion LOXL1

STOML1

PML

After insertion
SourcE: J.S. WElch E T AL/JAMA 2011
RARA

the mutations, it is incredibly hard to extract meaning from the alphabet soup of genetic errors. Pao and his Vanderbilt colleagues have built a new database that may help doctors decide which of the many mutations in a cancer cell are important, and which drugs to prescribe.

Right now, every time scientists compile a person’s genetic information, they have to sift through a mountain of data to find the changes that are driving that person’s cancer. “Every case is a research project,” Boguski says.

Spotting the drivers

Jerry Shay, a cell biologist at the University of Texas Southwestern Medical Center at Dallas, once wondered whether churning out reams of genetic data was even worthwhile.

“I started this thinking that we’d show
most of this stuff was rubbish, and we
were wasting money sequencing cancer
genomes,” he says. “I’m a complete turn-
around.”
Shay’s original problem with most
cancer genome studies was that they
came up with exhaustive lists of all the
ways that cancer cells are messed up
and then somebody had to make a rather
subjective decision about which of those
abnormalities was important. Instead of
guessing, he and his colleagues decided
to ask colon cancer cells.

Previous studies had estimated that 151 genes play a role in colon cancer. Only eight to 15 were thought to really drive the tumor — causing its out-of-control growth. The vast majority of mutations were thought to have happened incidentally and were like passengers on a runaway bus.

Shay’s team grew cells from the lining of the colon in lab dishes and then introduced mutations in two genes frequently involved in cancer, p53 and KRAS. But cells with mutations in either of those genes grew fairly normally, the researchers reported in the July Cancer Research. Then the researchers used a genetic trick to start knocking out each of the 151 genes one by one from colon cells that already carried either the p53 or KRAS abnormalities.

Instead of a bus with a few drivers and lots of passengers, Shay’s team found that 65 of the presumed passengers were anything but backseat drivers. Those mutations had a hand either directly on the wheel or were involved in biological processes with genes that did, encouraging the colon cells to grow like tumors. Of those, 49 sparked cancerlike behavior when paired with either p53 or KRAS mutations.

If the study were a Dr. Seuss book about colon cells, it might be called “Oh, the Places You’ll Go Wrong!” There could be 50 to 100 paths that lead a colon cell to cancer, not just eight to 15 as other researchers had thought, Shay says.

“The idea that cancer cells accumu-
late a lot of incidental mutations that
don’t mean much is not well-founded,”
he says. “It’s just not as simple as we’d
like to think.”
Finding so many genes steering can-
cer could be good news for treatment.
Right now, there is no way to stop KRAS
once it has run amok. But the right drugs
might persuade a codriver to hit the
brakes, Shay suggests. He says more tests
are needed to determine if other cancers
also have many drivers.

After compiling genetic blueprints of more than 400 tumors from 20 different types of cancer, Mardis and her colleagues have discovered that genome sequences can point to more than just a cancer’s driving mutations.

One thing Mardis and her collaborators have learned is that tumors are not monolithic entities. They contain many groups of cells, some with mutations that might render them immune to chemotherapy or targeted drugs. Even if such cells make up only 10 percent or less of a tumor, they could still cause the tumor to spread or cause a recurrence at the original tumor site. Mardis wants to determine just how many cells’ DNA needs to be thoroughly looked at to identify all the problem mutations.

“We’re not going to learn that information until we just go ahead and do it,” she says.

Moving genetic testing forward may also one day help reveal whether precancerous cells are going to turn into cancer, saving some people from unnecessary surgery while allowing others to shut down cancer before a tumor revs up. “People don’t really understand just how personalized cancer care is going to become,” Mardis says.

The personal touch is still on the horizon, though. Despite decades of openly declared war on cancer, researchers are still in the early phase of learning about the genetics behind the disease.

When it comes to cancer, says Ryan, doctors are in the same position they were in when he started working in 1988 at Columbia College of Physicians and Surgeons in New York City. “HIV was rampant. Every night I was on call we’d admit 10 people, and seven to eight of them had HIV.” Once the protease inhibitors came out in the mid-1990s, the university hospital no longer needed a floor for AIDS and tuberculosis. “It’s gone,” he says. “That’s what we want for cancer.” s