Questions and Answers About Estimating Cancer Risk in Ashkenazi Jews Who Carry a Specific Mutation in Gene Previously Associated with Colon Cancer

National Cancer Institute
Monday, 31 August 1998

1. What is the purpose of the study?

The purpose of the study published in the September issue of Nature Genetics was to determine whether Ashkenazi Jews having a specific mutation in the APC (adenomatous polyposis coli) gene have an increased risk of cancer. Ashkenazi Jews are from eastern or central Europe and comprise about 90 percent of the 6 million Jews in the United States.

Previous studies have shown that other mutations in the APC gene are associated with a form of hereditary colon cancer, known as Familial Adenomatous Polyposis (FAP). Patients with FAP develop multiple colon polyps at a young age, have a pronounced family history of colon cancer, and nearly all will develop colon cancer if preventative measures are not taken. APC mutations are also found in most colon tumors from patients with non-inherited (sporadic) colon cancer.

2. What was already known about this alteration?

Researchers at The Johns Hopkins Medical Institutions and the Howard Hughes Medical Institute reported last year in the Sept. 1, 1997 issue of Nature Genetics that a particular alteration, I1307K, in the APC gene was found in a high percentage of Ashkenazi Jewish colon cancer patients. This alteration is not normally associated with FAP and none of these patients had FAP.

The researchers found that 12 percent (22 out of 211) of these patients carried the alteration and nearly 30 percent (seven out of 25) of those with a family history of colorectal cancer were carriers. In addition, the mutation was present in 6 percent (47 out of 766) of Ashkenazim studied which would make it the most common genetic alteration now known in any ethnic group. (The mutation was not found in any of the 243 non-Ashkenazim studied.) The scientists estimated that people carrying this APC alteration have about a 20 percent to 30 percent lifetime risk of developing colorectal cancer, compared to 9 percent to 15 percent lifetime risk for Ashkenazim without the alteration.

The current study was carried out in a larger general Ashkenazim population to assess whether the previous findings could be replicated and to evaluate whether the alteration is related to the risk of cancer.

3. How was the study conducted?

For the current study, researchers from both the National Human Genome Research Institute and the National Cancer Institute used DNA samples collected in 1996 from more than 5,000 volunteers from the Washington, D.C., Ashkenazi Jewish community. The volunteers had varying degrees of personal and family cancer history and were participating in a study to estimate the risk of cancer associated with having three specific alterations in the breast cancer genes, BRCA1 and BRCA2. Greater than 95 percent of the participants gave consent for the researchers to use their anonymous blood samples in future studies of other genes. Only the consented samples were used in the current study.

The researchers tested the DNA from the stored blood samples to see which of the volunteers had the alteration. Then, using the personal and family cancer histories provided by the participants, the effect of the I1307K alteration on cancer risk was examined in two groups: the 5,000 volunteers themselves and the more than 26,000 first-degree relatives of the volunteers, both living and deceased. The scientists estimated the cancer risk by comparing: 1) the cancer histories of the volunteers with the alteration to the cancer histories of the volunteers without the alteration; and 2) the cancer histories of the first-degree relatives of the volunteers with the alteration to the cancer histories of the first-degree relatives of the volunteers without the alteration.

4. What were the findings?

This study showed that:

- 7 percent of the volunteers carried this alteration. This finding is consistent with the previous study in the Jewish population. (By comparison, the previous study did not find the alteration in 243 non-Jewish individuals.)

- people with the alteration seemed to have a slightly increased risk of colon cancer, breast cancer, and other cancers. The investigators estimated that, by age 70, 5 percent of carriers in the study would develop colorectal cancer, compared to 3 percent of non-carriers. They estimated that, among women, 17 percent of carriers would develop breast cancer compared to 14 percent of non-carriers by age 70.

The investigators cautioned that the findings from the study are uncertain because of the small number of carriers with cancer even in this large population.

5. How might the I1307K mutation cause cancer?

The mutation occurs in the DNA of the APC gene at nucleotide 3920; a T base (thymine) at this position has been replaced by an A (adenine). The I1307K alteration results in a substitution of the amino acid lysine (K) for isoleucine (I) at codon 1307 in the APC protein product. This type of alteration is not typically found in FAP patients.

However, the T to A change in the DNA creates a long tract of eight consecutive As; the normal (A)3T(A)4 DNA sequence becomes (A)8. This long tract of As creates an unusual stretch of DNA that is processed incorrectly by certain enzymes that replicate DNA during cell division, DNA polymerases. The result is that when cells divide and replicate their DNA, the enzyme errors produce additional mutations within and around the A tract. Therefore, the initial T to A alteration is thought to cause DNA instability, leading to subsequent mutations that may contribute to the development of cancer.

6. What are the implications of this research for the Jewish community?

These findings provide information that may be important for understanding how cancers develop. However, additional studies are necessary to clarify whether these results have clinical relevance for Ashkenazi Jews. The majority of people with the I1307K alteration, will not develop colon or breast cancer, and only a small proportion of Jewish individuals who develop these cancers will be carriers.

7. What is known about hereditary colon cancer?

About 130,000 cases of colorectal cancer are diagnosed in the United States each year and 15 percent to 20 percent have a hereditary component. Three types of hereditary cancer are seen clinically: FAP, where those affected develop multiple colon polyps at a young age, have a strong family history and nearly all will develop colon cancer if preventative measures are not taken; hereditary non-polyposis colorectal cancer (HNPCC) patients have at least three family members with a history of colorectal cancer and commonly develop cancers at a very early age; and familial colorectal cancer (FCC), where patients are usually in their 50s or 60s when diagnosed and typically have one or two family members with a history of colon cancer or precancerous polyps.

FAP is the least common of the inherited colon cancers, accounting for less than 1 percent of the cases and is known to be caused by mutations in the APC gene where no functional protein is produced. HNPCC accounts for less than 5 percent of hereditary colon cancers and is known to be caused by at least four defective mismatch repair genes (most commonly MSH2 and MLH1). FCC is the most common form of hereditary colon cancer, accounting for about 10 percent to 20 percent of the cases. The genetic basis of the disease has not been well established, but is likely to involve multiple genes.

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