For years it has been known that pancreatic cancer is more common in Jews than in the general population (1-5). This increased risk is greater in Ashkenazi Jews (those of European origin) than it is in Sephardic Jews (those of Asian or African descent) (6). While this increased risk could be due to a variety of factors such as diet and cigarette smoking, a growing body of evidence suggests that a significant portion of the increased risk of pancreatic cancer in individuals of Ashkenazi Jewish descent has a genetic basis. By this we mean that these cancers are caused by inherited ("germline") changes ("mutations") in specific cancer associated genes. Scientists at Johns Hopkins are actively working to identify these genes and are developing therapies that specifically target cancer cells with mutations common in pancreatic cancers in the Ashkenazi Jewish population.
If you are of Ashkenazi Jewish ancestry and have pancreatic cancer or a family history of pancreatic cancer, please consider participating in one of our research studies. To learn more about how you can help please contact David Huang.
The second breast cancer gene is called BRCA2 (7). Since its discovery in December of 1995, researchers have come to a better understanding of the role of the BRCA2 gene in the development of cancer. Every cell in our body has two copies of BRCA2. One is inherited from our mother and one from our father. It turns out that an ancestor of Eastern European Jews, approximately 29 generations or 3000 years ago, developed a defect in the DNA coding for the BRCA2 gene (8). This DNA defect, known as the 6174delT mutation, has been passed from generation to generation. As a result, 1% of all Ashkenazi Jews living now inherit a defective copy of one of their BRCA2 genes (9). Unbeknownst to them, these carriers of the BRCA2 mutation are at increased risk for developing breast, ovarian, prostate and pancreatic cancer (10;10-17).
The risk of cancer to Jews who inherit a defective copy of the BRCA2 gene varies in different families. The reason for this variation in risk is thought to be dependent on "lifestyle factors" such as smoking, dietary influences, the inheritance of other cancer susceptibility genes, and a certain element of chance. In addition, because the risk of cancer in a BRCA2 mutation carrier continues throughout life, we will see more cancers caused by inherited BRCA2 mutations as our population ages.
While most attention in the media has been given to the risk of breast and ovarian cancer, carriers of the BRCA2 gene mutations also have a ten-fold increased risk of developing pancreatic cancer (10;10-17). Current evidence suggests that in Jewish individuals who develop pancreatic cancer approximately 1 in 10 such cancers are caused by inherited BRCA2 gene mutations (10;11). Put another way, carriers of BRCA2 mutations have a 1 in ten to 1 in 20 chance of developing pancreatic cancer by the age of 80. Indeed, the discovery of the BRCA2 gene was greatly facilitated by the discovery of a unique genetic alteration in a pancreatic cancer by scientists at The Johns Hopkins Hospital (18).
One striking feature of carriers of mutations of the BRCA2 gene is that they may not suspect that they are carriers because they may not have a family history of cancer, despite the fact that their ancestors on one side of their family must also have carried the same mutation (19). There are many reasons for this subtlety. Not every individual with an inherited BRCA2 gene mutation will develop cancer. As mentioned above other genetic and environmental factors influence the risk of developing cancer. A small family size or early death from other causes may also obscure a familial cancer predisposition. In addition, males with BRCA2 mutations may have a lower risk of developing cancer and they may therefore obscure a familial cancer predisposition. Clearly, the absence of a family history of cancer does not mean that one does not carry the BRCA2 gene mutation.
The first breast cancer gene to be discovered is called BRCA1, and inherited (germline) mutations in BRCA1 increase the risk of breast, ovarian, uterus, cervix, pancreatic, and maybe prostate cancer (20;21). Approximately one and a half percent of the Ashkenazi Jewish population carries an inherited mutation in the BRCA1 gene (6). These mutations are usually of one of two types, called the 185delAG and the 5382insC mutations (22). The increased risk of pancreatic cancer associated with inherited BRCA1 mutations is estimated to be about two-fold (about the same increased risk associated with cigarette smoking) (20;21).
As was true for BRCA2 mutations, the risk of cancer to Jews who inherit a defective copy of the BRCA1 gene varies in different families. The reason for this variation in risk is thought to be dependent on "lifestyle factors" such as smoking, dietary influences, the inheritance of other cancer susceptibility genes, and a certain element of chance.
The BRCA1 and BRCA2 genes encode for proteins that function in the "Fanconi's anemia" pathway within normal cells (23-25). This cellular pathway functions to repair certain types of damage to DNA (called DNA cross-linking damage). Cells that are defective in BRCA1 or BRCA2 are known to be highly sensitive to certain chemicals. Indeed, Dr. Kern and colleagues from Johns Hopkins have found that BRCA2-deficient pancreatic cancer cells are especially susceptible to the toxic effects of the anticancer drugs mitomycin and cis-platin. This finding suggests that specific therapies could be targeted to specific patients depending on their BRCA1 and BRCA2 gene status. For example, pancreatic cancers caused by an inherited mutation in BRCA1 or BRCA2 may specifically be sensitive to treatment with one of these drugs (23-25). More research in this exciting new area is underway.
Screening of pancreatic cancer families to detect early pancreatic tumors The early detection of cancer has proven to be an effective means of reducing the risk of dying from several types of cancer. At Johns Hopkins, we have begun screening asymptomatic (without symptoms) individuals known to be at increased risk of developing pancreatic cancer (because several members of their family developed the disease) for evidence of cancer or pre-cancerous changes in their pancreas (26;27). Screening the pancreas involves imaging the pancreas with techniques such as endoscopic ultrasound (EUS) or CT scanning. We have identified precancerous tumors of the pancreas in several family members that were completely and safely removed with surgery, raising hopes that screening for early pancreatic cancer is possible in families burdened by a propensity to develop pancreatic cancer (28).
Research scientists at Johns Hopkins are actively hunting for other genes that may increase the risk of pancreatic cancer in the Ashkenazi Jewish population. If you have an interest in joining our research study please contact David Huang.
Clinical tests are now available for both BRCA1 and for BRCA2 gene mutations. Although these tests are available, they may not be right for everyone. In deciding whether or not you want to have a gene test performed, you should speak with a trained genetic counselor so that you are fully informed of the issues at stake. Genetic counseling includes both pre-test and post-test counseling, and can be given by specialist genetic counselors or by physicians experienced in this area. Genetic counseling is important before one embarks on gene testing because although gene testing raises concerns about insurance liability and employer discrimination, knowledge of one's risk can empower an individual. A negative result can provide reassurance, while positive result may save a life through the early detection of cancer or possibly even with preventative surgery.
To learn more about genetic testing or if you have any questions, please contact Jennifer E. Axilbund, M.S.
A good site on genetic diseases in the Ashkenazi population: www.jewishgeneticscenter.org