Colon Cancer Cases Show Dilemmas of Genetic Testing

BALTIMORE—A series of colon cancer case studies presented at a meeting on clinical cancer genetics at Johns Hopkins University illustrated the complexity, medical and otherwise, that accompanies genetic testing for cancer.

Could it Be FAP?

In the first case, a 20-year-old woman was found to have colon polyps and was diagnosed with stage IV metastatic colon cancer. She also had a sebaceous cyst on her leg and unerupted teeth. She received surgery, chemotherapy, and radiation for the cancer, but was not doing well.

“Could her diagnosis be familial adenomatous polyposis (FAP),” asked Karen Johnson, MS, CGC, a genetic counselor at the Johns Hopkins Oncology Center. The woman’s father had a negative family history, but her mother had had a sigmoid colon resection for treatment of diverticulosis.

“While a family history is important,” Ms. Johnson said, “a negative history does not rule out the diagnosis. Thirty percent of all mutations occur de novo.”

Ordinarily, if neither of the parents of an affected person has the mutation, familial disease in the siblings can be ruled out. However, there is still a possibility of germ-line mosaicism, ie, the mother could have the mutation in her eggs but not in her own cells. She added, however, that no case of germ-line mosaicism has ever been documented in FAP.

Once the woman’s FAP diagnosis was confirmed, she expressed fear for the vulnerability of her two young children. “FAP is a disease of the young,” Ms. Johnson said. “Many start to develop polyps in their teens; 95% have them by their 30s.”

Frank Giardiello, MD, associate professor of gastroenterology, Johns Hopkins, pointed out that although there have been case reports of the disease in children as young as 7 or 8, the curve skyrockets in the 20s, and the mean age of diagnosis is 39. “Try to find and test kids in their teen years,” Dr. Giardiello advised.

Ms. Johnson said that “if the test is sensitive for one family member, it will be sensitive in testing others.” There is a 50% chance the patient could pass along the mutation to her children, she noted, so the issues surrounding early testing are as much emotional and social as medical. “Some parents want to test children as young as 1 or 2 years,” she said, “but is that appropriate?”

She also asked the audience to think how the mother might feel if she discovered she had—or had not—passed along the mutation. “Would the family treat a child who tested positive differently?” she asked. “What about the patient’s mother, who would become the children’s guardian if the woman died?”

If the patient had a de novo mutation, then her siblings would have only the same risk as the general population and require standard screening at age 50. “But,” Ms. Johnson said, “relatives are often not reassured by that fact. They may still perceive themselves as being at risk and continue screening anyway.”

An Ashkenazi Jewish Family

In another case, a 52-year-old Ashkenazi Jewish woman was found to have two polyps and wanted genetic testing to help her decide on future screening. Six percent of Ashkenazi Jews have the I1307K mutation, predisposing them to increased risk of colorectal cancer.

“How would genetic testing impact recommendations for screening?” asked Jill D. Brensinger, MS, CGC, also a genetic counselor at Johns Hopkins. A positive test, for instance, would indicate the need for colonoscopy every 2 years. However, this patient was already being screened every 3 years. “The difference in screening every 2 or every 3 years may not be significant,” she said.

The I1307K test indeed proved positive, prompting the woman’s sister to inquire about taking the test. “Since she was asymptomatic, there were several potential downsides to genetic testing,” Ms. Brensinger said. The sister would have to discuss with her children the effects and implications of a positive test. Her own screening pattern might alter, although she had Crohn’s disease and was being screened every 2 years anyway.

Ultimately, the sister decided against testing for the reason many patients give: fear of insurance discrimination. The woman—a widow—felt she would rather live with the uncertainty than risk being without coverage for herself and her two children.

HNPCC: Which Test to Use?

A third case illustrated other issues with genetic testing. A 55-year-old woman was diagnosed with colon cancer and underwent a right hemicolectomy. She had a heavy family history of cancer. Both siblings had colon cancer, and a daughter was diagnosed with the disease at age 25.

To confirm a diagnosis of hereditary nonpolyposis colon cancer (HNPCC), Ms. Johnson suggested microsatellite instability (MSI) testing 92% of HNPCC colon tumors have MSI, but 8% of such tumors are stable, despite the presence of a germ-line mutation. “So you might skip MSI testing in families with a very strong colon cancer history and go straight to germ line,” she said.

What were the preventive options for the woman’s children? Physicians recommended a subtotal colectomy for the daughter with colon cancer. Her son, who had a polypoid colon mucosa lesion, faced a tougher decision. He could be tested and, if mutation positive, might consider a prophylactic colectomy. However, HNPCC has only an 80% penetration among bearers of the mutation, so onset of the disease is not inevitable.

“Only about a dozen people in the United States have opted for a prophylactic colectomy on the basis of genetic testing,” Ms. Johnson said.