BALTIMOREA 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
Could her diagnosis be familial adenomatous polyposis
(FAP), asked Karen Johnson, MS, CGC, a genetic counselor at the
Johns Hopkins Oncology Center. The womans 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 womans 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
She also asked the audience to think how the mother might feel if she
discovered she hador had notpassed along the mutation.
Would the family treat a child who tested positive
differently? she asked. What about the patients
mother, who would become the childrens guardian if the woman
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
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 womans
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 Crohns
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 womana
widowfelt 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 womans 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.