Thanks to advances in genetic medicine, DNA tests can now determine your risk for some cancers, giving doctors powerful fortune-telling tools for prevention and treatment.

by Monika Guttman, Alicia Di Rado and Lori Oliwenstein

photo illustrations by Chip Simons

Elaine Henson was not your typical candidate for genetic testing to detect the so-called “breast cancer genes,” BRCA-1 and BRCA-2. A 42-year-old mother of two from Lake Havasu, Nevada, she has no real family history of the disease. None of her four sisters, mother, grandmothers or some 13 female cousins on her father’s side had had it.

But in September 2000, Henson herself was diagnosed with a rather aggressive form of cancer in her right breast. After a mastectomy and a round of chemotherapy, her doctor, USC oncologist Christy Russell, suggested that Henson consider genetic testing to determine whether she had one of the breast cancer genes. If she did, Russell explained, the chance of a cancer recurrence in her left breast jumped from around 20 percent to more than 80 percent.

When Henson – who works as a nurse-practitioner – heard that, she didn’t hesitate. “I couldn’t imagine not having [the test],” she says, “and going on with a false sense of security, then two years later having the cancer appear on the other side and having it be metastatic.” To get more information, she made an appointment with Monica Alvarado, a genetic counselor at the USC/NorrisComprehensive Cancer Center’s Lynne Cohen Clinic. Just what was the likelihood that she had BRCA-1 or BRCA-2? Based on the lack of family history, Alvarado told her, the probability was somewhere between 7 and 17 percent. “It just didn’t seem likely,” Henson says, but she went ahead with the testing anyway.

Turns out Henson belongs to the statistical minority. Last January, she got back positive results for BRCA-2. A few weeks later, to eliminate her high risk for more cancer, she had another mastectomy, this time of her left breast. She also had a preventive hysterectomy, because women with BRCA-1 or BRCA-2 have a 50 percent increased risk of developing ovarian cancer. One of Henson’s aunts had recently been diagnosed with that disease, and from her professional experience, Henson knew first-hand how hard that cancer is to detect and treat.

For Henson, knowing and doing something about her risk was better than waiting.

“At least I can say I’ve done everything I can to make sure I don’t die from this disease,” she says.

USC/Norris director Peter Jones
Welcome to the brave new world of genetic testing, where individuals like Elaine Henson can choose to know whether or not they have a predisposition to cancer. Until now, the most common use of genetic testing has been for diagnostic purposes (to check whether a fetus has any genetic defects, or to study mutations in a particular cancer tumor to help guide treatment). But genetic tests are gradually becoming available as predictive tools for many diseases, including cancer. In addition to BRCA-1 and BRCA-2, genetic mutations have been identified for several other cancers, including colon cancer, melanoma and some types of lymphoma (a mutation in the CDKN2
gene on chromosome 9).

Interest in genetic tests for cancer risk in particular is enormous. Cancer is the second leading cause of death in the United States (after heart disease) and will strike more than 550,000 people this year alone, according to the American Cancer Society. As in Henson’s case, genetic testing could alert those who have no family history of the disease and could revolutionize health care aimed at cancer prevention.

“We’re at the beginning of the age when we can predict for cancer risk,” says Peter Jones, director of the USC/ Norris Comprehensive Cancer Center. “There’s enormous interest in this field, and it is an increasing part of our work here. This is something that could really make a difference.”

Despite great interest, no one is expecting an enormous rush to testing. For one thing, the tests have raised a host of moral, ethical and legal questions that will take years to sort out. Until test-result privacy can be guaranteed, many Americans fear taking a genetic test could have negative consequences on employment (because health insurance is primarily obtained through a job), as well as on health- and life-insurance costs. Some fear it may lead to sweeping changes in insurance coverage: based on genetic tests, will insurers demand (and only pay for) preventive measures, not treatment of the disease itself?
"We’re at the beginning of the age when we can predict for cancer risk. There’s enormous interest in this field, and it is an increasing part of our work here. This is something that could really make a difference.”

Privacy isn’t the only impediment. By current estimates, each individual carries about five mutations that predispose him or her to a lethal disease. Almost everyone, therefore, would have to deal with some bad news if tested – and not everyone wants that headache.

Elaine Henson understands this very well. Discovering you have a cancer gene, she says, is “the most devastating thing you can imagine. The emotional upheaval is enormous.”

And then there is the decision about how to actually use the results. Some, like Henson, take aggressive preventive action, while others find themselves deeply conflicted. In Henson’s own family, news of her genetic predisposition to breast cancer prompted two of her four sisters to get tested themselves; the other two didn’t want to know. One sister’s test has come back positive for BRCA-2, and she is now struggling with her options.

We are still years away from having a standardized test to determine each individual’s cancer risk, says Jones, a biochemist and molecular biologist in the Keck School of Medicine of USC.

Genetic testing for cancer predisposition is still a fairly new science. It dates back to 1982, when a deletion of part of chromosome 3 was first observed in cancerous cells from certain lung tumors. The much-ballyhooed discovery in the early 1990s of BRCA-1 and BRCA-2 led to a prediction that, with the deciphering of the human genome, we would soon pinpoint the specific rare mutations that are the harbingers of all cancers.

This hope was bolstered by the discovery, in the mid-1990s, of mutations on p53 – a tumor-suppressor gene (one that naturally blocks the formation of tumors). The mutations are found in most tumor types, and p53 has been hailed a key player in the complex network of molecular events leading to tumor formation. A person inheriting only one functional copy of the p53 gene – a rare congenital deficiency called Li-Fraumeni syndrome – is predisposed to cancer and usually develops several independent tumors in early adulthood.

Scientists are coming to realize, however, that most cancer is not caused by one easily identified mutation.

“We know there are two kinds of genetic approaches” to the body’s tendency toward cancer, says Jones. The first involves rare genetic mutations that signal a fair probability that the carrier will develop cancer.

BRCA-1 and BRCA-2 fall into this group. “In certain defined cases, those tests can be very, very helpful,” Jones says.

But scientists have also discovered other genes – with more common small bits called “polymorphisms” – that in and of themselves don’t lead to cancer, but do contribute to making conditions ripe for the disease.

“Researchers are trying to develop [tests for] these genes, but we’re still quite a ways away,” Jones says. “We’re just beginning to work on it.”

What that means for patients, according to USC/Norris genetic counselor Alvarado, is that at present “there’s no easy answer to the question of any individual’s risk for cancer.”

And for researchers, it means wading through enormous amounts of genetic data in search of specific clues.

One such molecular sleuth is Heinz-Josef Lenz, USC/Norris scientific director of cancer genetics. Not long ago, Lenz and his colleagues identified a polymorphism that might tip them off to who is and isn’t likely to get colon cancer at an early age.

Lenz and his team examined a gene that’s related to a protein in the body called manganese superoxide dismutase, or MnSOD. This protein is one of the body’s key chemical fighters against oxidative stress – a known factor in cancer and other diseases.

If your MnSOD gene works well, the MnSOD protein your body produces can effectively scavenge and neutralize oxidative radicals that damage human cells.

But if you have a certain polymorphism of this gene, your body produces a slightly different kind of MnSOD that researchers believe packs a less protective punch. People with this polymorphism may not be as shielded from cellular damage as others, and may be more likely to get colon cancer at a young age, says Lenz.
The MnSOD gene isn’t the only one responsible for early-onset colon cancer, however. Lenz’s group also is exploring the role of the XRCCI gene, a crucial player in DNA repair. The researchers are looking at the frequency and significance of XRCCI polymorphisms and are gathering data to show its potential role in colon cancer.
The gene appears to predict resistance to chemotherapy, too. By testing for an XRCCI polymorphism in colon cancer patients, doctors may soon know in advance that a particular tumor would resist certain drugs, and opt for other, more potent drugs instead.

Photo by S. Peter Lopez

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