By: Marilyn Lewis

Reviewed by Peggy Conrad, MS, CGC

When Janice MacAfee learned that the cancer which had plagued her family for generations might be caused by a malfunctioning, or mutated, gene that she had inherited from her mother, her first thought was, "Should I get a gene test?" As Janice was soon to find out, this is a complicated question — and one she could consider only in the context of her entire family.

Janice MacAfee

At age 58, and twice diagnosed with cancer, Janice had nothing to gain personally from getting a DNA test. Because of her personal and family medical history, Janice's doctors were already convinced that she had inherited the cancer-causing syndrome called hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome) and that she needed to practice vigilant and frequent cancer screening. A genetic test would only confirm those findings.

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If Janice could find out the genetic culprit for her cancer, other family members could be tested for the same mutation.

However, Janice wasn't thinking only about herself. She understood that if doctors were able to identify the genetic culprit for her cancer, other family members could be tested for the same genetic mutation.

Family members who tested negative would be freed not only from fear of the disease but also from a lifetime of intensive, and generally unpleasant, screening. Family members who tested positive for the mutation would receive an early warning that could quite possibly save their lives.

Either way, Janice's willingness to be tested was the key to isolating and identifying the family's inherited cancer syndrome — and to opening up a discussion of the unusual syndrome that afflicted her family.

This is the story of how Janice and genetic counselor Peggy Conrad, at the University of California, San Francisco, worked together to give Janice's family more control over the cancer that runs in their genes.

The MacAfee Family's Medical History

Janice's mother, grandmother, two of her aunts, and two of her first cousins had all died of cancer.

The chaos caused by the loss of her mother deeply affected Janice, the eldest of the seven children. Although over time she made a happy and productive life — becoming a schoolteacher, marrying, and giving birth to three children (Adam, Olivia, and Caroline) — cancer was always in the back of her mind. Says Janice, "I just figured, my mom had it and I would have cancer." She felt doomed — a sentiment not uncommon among families with HNPCC, according to Conrad.

A Prophecy Fulfilled

When two of Janice's sisters also died of cancer, she was grief stricken. Then, Janice herself was diagnosed with uterine cancer.

"Many women in the family had hysterectomies," says Janice. "If they didn't, they died of uterine cancer." Not surprising, since we now know that endometrial cancer (cancer of the lining of the uterus) is one of the diseases that show up frequently among families with HNPCC.

Janice's doctor concluded that there must be a genetic component to the cancers in their family.

Janice's doctor was aware of her family's medical history. Years earlier — before Janice herself was diagnosed with cancer — she had told him about her family's experience with the disease. Citing the early age of onset and the multiple affected family members over several generations, Janice's doctor concluded that there must be a genetic component to the cancer cluster in her family. However, 20 years ago, scientists had not yet discovered any of the HNPCC-associated mutations, so genetic testing was out of the question.

Although Janice's doctor didn't know the precise genetic culprit for her family's cancer, he knew enough to realize that Janice was at increased risk for at least colon cancer. Thus, at his urging, Janice had been undergoing regular screenings for colon cancer as part of her health care routine — at first by sigmoidoscopy and then later by the more thorough colonscopy, which doctors have now come to recommend for people with a family history of colon cancer.

Janice survived her uterine cancer, only to be diagnosed with colon cancer eleven years later.

Janice endured her uterine cancer with stoicism. Then, 11 years later, she found out she had colon cancer. One of those routine screening exams had revealed a polyp in Janice's colon, which doctors then determined to be cancerous. To be safe, Janice's doctor recommended that she have a third of her colon removed.

Having a large part of her colon removed gave Janice a better chance of being disease free in the future.

Janice was aghast. Although removal of a portion of the colon is the most common treatment for colon cancer, doctors often recommend removing a larger segment in colon cancer patients who have a hereditary risk for colon cancer. Janice's doctor also told her about (although did not necessarily recommend) a more controversial option called a colectomy, in which the entire colon is removed. Janice thought the matter over carefully and decided to have a large part of her colon removed.

However, her vigilance couldn't end there. For people at high risk, like Janice, colon cancer can occur again, in a different part of the colon.

From Worry to Action

As she coped with her own cancers, Janice wondered what she could do to protect her children. She also felt the eldest child's sense of responsibility toward her siblings and their children. But there was little much she could do, besides worry.

Janice recognized the pattern of her family's cancer as Katie Couric talked about the syndrome called HNPCC.

Then, one evening in 1998, she turned on the television and saw Today Show host Katie Couric talking about losing her husband — a relatively young man — to hereditary colon cancer. As Couric described the HNPCC syndrome, the pieces of Janice's puzzling family history began for the first time to assume a coherent shape. "That's us!" she told her husband, Jack.

After doing further research on the web, Janice approached her doctor, printouts in hand. Convinced that her children's lives were at stake, Janice told her doctor, "I want to be tested for this gene."

Janice wanted to undergo genetic testing for the HNPCC gene, so her doctor referred her to a genetic counselor.

The genetic counselor listened as Janice recounted her family's history of cancer. She and Jack learned about the genetics of HNPCC and the risks and benefits of genetic testing. They also discussed with the counselor their fears about how a positive result — that is, the discovery of a malfunctioning gene — might affect their immediate and extended family.

Janice worried about the test. She hoped she tested positive so her family members could find out if they carried the gene.

But, what if the test was inconclusive? This was a risk she was willing to take. By now Janice knew she had HNPCC and her family members were at risk for cancer whether they could find the gene mutation or not. After much discussion, Janice had blood drawn, and sent to a laboratory for analysis.

Answers

Although the geneticists in the lab where Janice's blood was sent were not exactly searching for a needle in a haystack, they did need to look at several genes associated with HNPCC — a time-consuming and expensive process. An initial series of gene tests cost between $800 and $1,600. Once a mutation has been isolated, however, the cost of testing drops to $200 to $400 for other family members since lab workers now only need to examine one gene — the one in which they've already identified a mutation.

Janice's first test results were no help to her family...a mutation could not be found.

Using newer testing methods, an HNPCC-associated mutation was finally found.

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Aftermath

Janice's daughters, Olivia and Caroline, got tested for the mutation, however her son, Adam, did not.

Olivia was distraught at the thought that she may have passed on the family cancer gene to her daughter, Jessica. She wanted to know if Jessica had the gene as well. Olivia's genetic counselor explained that because the cancers associated with HNPCC generally do not occur in children, genetic testing is not recommended. Sharing family information about cancer risk with Jessica as she matures is important, because when she becomes a young adult, she will be able to personally decide if she wants to learn her genetic status.

Caroline, 21, also chose to get the test. For her, curiosity was a factor. She simply couldn't imagine not knowing, Her result: negative. For Caroline, Janice's gift was a lifetime of normalcy. Although the absence of the mutated gene doesn't reduce Caroline's colon cancer risk to zero — no one's risk is that low — it does mean that her chances of developing the disease are no greater than anyone else's.

Adam shunned testing for fear of employment or insurance discrimination. He just assumes he is at risk and gets regular screening.

Adam, 28, a graduate student at a major university, made a different choice. Foreseeing a career in which he would be working for a number of different companies, he saw cause for concern. Although there's little documented evidence of employers or insurers shutting people out of jobs or insurance because of genetic test results, as Adam told his parents, genetic testing is pretty new. He worried about what would happen down the road if he were to test positive for a gene mutation.

Adam decided not to get the test — for the time being. Instead, he will assume he has the mutation and, like Olivia, follow a faithful regime of colonoscopies, which are likely to be covered by his insurance given that he has a family history of the disease.

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