Small Cancer Risk May Be Associated with Alteration in APC Gene

National Cancer Institute
Monday, 31 August 1998

Researchers at the National Human Genome Research Institute (NHGRI) and the National Cancer Institute (NCI) have found that people with a specific alteration in the APC gene, I1307K, may develop cancer at a slightly higher rate than those with normal APC genes. The findings appear in the September issue of Nature Genetics*.

Specifically, they found a slightly increased risk of cancer in I1307K carriers, mostly due to an increase in colon and breast cancer. The investigators estimated that by age 70, 5 percent of carriers would develop colorectal cancer, compared to 3 percent of non-carriers. Among women, 17 percent of carriers would develop breast cancer compared to 14 percent of non-carriers by age 70.

APC is a gene that normally suppresses the growth of colon tumors and its protein product is thought to play a role in control of the cell cycle by regulating the expression of other genes. Abnormalities in APC have been linked to familial adenomatous polyposis (FAP), an inherited disorder characterized mainly by intestinal polyps that become cancerous unless surgically removed.

Last year, researchers at the Johns Hopkins University in Baltimore, discovered that the I1307K alteration was present in a high proportion (30 percent) of Ashkenazi Jewish colon cancer patients with a family history of colon cancer. None of these were FAP patients and this alteration is not normally found in FAP patients. The I1307K variant was found in 6 percent of control Jewish individuals.

Although researchers have long known that severe APC alterations cause colon cancer, the I1307K variant appears to make the DNA segment containing this change more prone to develop additional alterations.

NIH scientists estimated the risk of several cancers in people who possess the APC I1307K alteration. Their study population comprised more than 5,000 Washington-area Jews of Eastern European descent (known as Ashkenazi Jews) who participated in a study in 1996 to analyze the breast cancer risk associated with mutations in breast cancer genes. The researchers examined the DNA from volunteers who agreed to have their blood used for the gene study to see who carried the alteration. The scientists also estimated their risk of colon, breast, and other cancers based on their family and personal histories. The DNA samples were rendered anonymous prior to testing.

Ashkenazi Jews are one of several populations helpful to such genetic studies because they can trace their roots to a small founding population. Some specific genetic variants may be studied in this group because they are present at a higher frequency than in the general population. Other variants are found only infrequently in the Jewish population compared to other groups. There is no evidence that genetic disorders are more common in this group than any other. The frequency of APC I1307K has not yet been thoroughly studied among non-Jews, but it is believed to be rare.

The scientists believe the findings, while not yet useful for medical testing or treatment, may provide cancer researchers clues about how tumors arise. Further studies are needed to verify the findings.

In a second paper in the same issue of Nature Genetics, another group of researchers looked to see if the I1307K mutation was associated with an increased the risk of breast cancer by examining 632 North American Jewish women with breast cancer. The study revealed that 66 of the women -- or just over 10 percent -- carried the APC I1307K alteration, compared to the 7 percent expected frequency found in the Washington-area study population. The paper also reports that of the 91 women in the study population who possessed either a BRCA1 or BRCA2 mutation, well-known breast cancer genes, 16 were also APC I1307K carriers.

Both results were statistically significant, but the authors suggested "that the effect of the I1307K allele is largely -- or entirely -- limited to those with BRCA alterations." The researchers concluded that APC I1307K may either be a gene that increases susceptibility to breast cancer by, at most, a small amount, or perhaps modifies the risk in women with a BRCA alteration. "For the substantial majority of individuals of Ashkenazi Jewish background, clinical testing for the I1307K allele is not justified outside of a research context," they concluded.

For more information, or to contact National Cancer Institute, see their website at: www.cancer.gov