Alison Klein and Jim Eshleman

Our Research

You may be wondering why joining this study is helpful and how we are using the information in the registry.

While the causes of most pancreatic cancer remain unclear, we do know that approximately 5-10% of all pancreatic cancers run in families. (Click here for more information on the genetic aspects of pancreatic cancer.) Other risk factors for pancreatic cancer include cigarette smoking and obesity.

Gathering information from families like your own provides scientists with a unique opportunity to study the cause of pancreatic cancer. This information may ultimately help devise new ways to find pancreatic tumors earlier and develop better treatments for pancreatic cancer.

The primary goals of our research are to:

  1. Understand the risk of pancreatic cancer in families.
    When the registry began in 1994, few people recognized the importance of the familial clustering of pancreatic cancer. Since its beginning, the registry has led the way in demonstrating that pancreatic cancer does cluster in families and that there is likely to be a genetic cause of this clustering. Our work has demonstrated that individuals from familial pancreatic cancer families have a nine-fold increased risk of developing pancreatic cancer. Thus, our research has provided the foundation for genetic counseling and screening for pancreatic cancer. Currently, we are working on ways to improve clinical risk assessment. We developed a tool called PancPRO for health care providers. This tool allows for risk assessment to be tailored to each individual's family history.
  2. Identify genetic and non-genetic causes of pancreatic cancer.
    We have been working to better understand the causes of pancreatic cancer. We have demonstrated that mutations in BRCA2, PALB2, and ATM genes are responsible for the clusters of pancreatic cancer in some families. The genetic basis of most pancreatic cancers, however, remains unclear; therefore we are actively searching for additional pancreatic cancer genes. Currently, we are using the latest high-throughput gene sequencing and genotyping technologies to identify pancreatic cancer genes. In addition, we collect information on lifestyle factors that may influence pancreatic cancer such as cigarette smoking, medical history of diabetes and pancreatitis, and environmental exposures.
  3. Facilitate the early detection of pancreatic cancer.
    The NFPTR has been working to improve the early detection of pancreatic cancer. Our early studies have shown that individuals with a family history of pancreatic cancer represent a high-risk group that may benefit from early detection screening. In 1998, our partnership with Dr. Canto's early detection screening trials (CAPS) began, and recently the fourth stage of this study, CAPS 4, has concluded. They are currently recruiting for the fifth stage of their study. Additionally, we are working with Dr. Michael Goggins' Early Detection laboratory as well as the Pancreatic Cancer Detection Consortium (NCI) on the development of diagnostic and early detection bench markers for pancreatic cancer.

Related Areas of Research

As part of our research, we are conducting focused studies on populations found to be at a higher risk of pancreatic cancer.

Ashkenazi Jewish Population   

Pancreatic Cancer and Ashkenazi Jews

Individuals of Ashkenazi Jewish ancestry have an increased risk of developing pancreatic cancer. Most causes of this increased risk are unclear however, a portion of this increased risk is due to mutations in the BRCA2 and BRCA1 genes.

Scientists from the NFPTR at The Johns Hopkins Hospital are actively working to identify the genes in Ashkenazi Jews and other risk factors that may account for the increased risk of pancreatic cancer. You can help our research by joining the NFPTR.

BRCA2
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 ago, developed a defect in the DNA coding for the BRCA2 gene. 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. Unbeknownst to them, these carriers of the BRCA2 mutation are at increased risk for developing breast, ovarian, prostate and pancreatic cancer.

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. Current evidence suggests that in Jewish individuals who develop pancreatic cancer approximately 1 in 10 such cancers are caused by inherited BRCA2 gene mutations. In other words, carriers of BRCA2 mutations have a 1 in ten to 1 in 20 chance of developing pancreatic cancer by the age of 80. 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.

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. 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.

BRCA1
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. Approximately one and a half percent of Ashkenazi Jews carry an inherited mutation in the BRCA1 gene. These mutations are usually one of two types, called the 185delAG and the 5382insC mutations. 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).

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.

Treatment Implications
The BRCA1 and BRCA2 genes encode for proteins that function in the "Fanconi's anemia" pathway within normal cells. 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. Dr. Scott 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. More research in this exciting new area is underway.

Screening of pancreatic cancer families to detect early pancreatic tumors 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. 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.

Other Genes
Research scientists at Johns Hopkins are actively hunting for other genes that may increase the risk of pancreatic cancer in the Ashkenazi Jewish population.

Genetic Testing
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. 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.

A good Web site on genetic diseases in the Ashkenazi population is: http://www.jewishgeneticscenter.org

African American Population   

Pancreatic Cancer and African Americans

Pancreatic cancer is the fourth leading cause of cancer death in the United States and the fifth leading cause of cancer death worldwide. Cancer of the pancreas accounts for only about 3% of the cancers diagnosed each year. However, the five-year survival rate is approximately 9%, making pancreatic cancer a leading cause of cancer death. The incidence of pancreatic cancer is 23-52% higher in African Americans than in any other racial group in the United States. Not only is pancreatic cancer more common among African Americans, but African Americans are more often diagnosed with advanced, and therefore, inoperable cancer. African Americans also are less likely to undergo evaluation by a surgeon, and less likely to receive surgery than any other racial group in the United States.

If you or your family member has pancreatic cancer and would be interested in being evaluated at our multi-disciplinary pancreatic cancer clinic, please click here.

Many studies have been conducted to determine why there is an increased risk of pancreatic cancer among African Americans. These studies suggest that environmental and socioeconomic factors may be important. Cigarette smoking, which causes about 25% of pancreatic cancer, is more common among African Americans and therefore may partially explain why pancreatic cancer is more common in African Americans. Other risk factors for pancreatic cancer that are more common in African Americans include diabetes mellitus, pancreatitis, and being overweight. The research team at the NFPTR is interested in determining why African Americans are at higher risk of pancreatic cancer. You can help by participating in our research studies.


Additional Risk Factors

Cigarette smoking is the most preventable cause of pancreatic cancer. Cigarette smoking accounts for 25-30% of pancreatic cancers. Smoking cigarettes doubles the risk of pancreatic cancer, regardless of race. Smoking rates among African American adults historically have been higher than among the general U.S. population. However, in recent years smoking rates for blacks and whites are similar. Cigarette smoking is the most preventable cause of pancreatic cancer.

Diet: The risk of pancreatic cancer is elevated in diets high in fat and calories. Processed meat high in nitrates, such as bacon and bologna, also increase the risk. The human body may process nitrates into cancer causing chemicals, called carcinogens.

Body Mass Index: The risk of pancreatic cancer increases with body mass, regardless of racial group. However, it has been observed that obesity is more common among African Americans as compared to other racial groups. This may help to explain the increased incidence of pancreatic cancer among African Americans.

Diabetes Mellitus: Blacks are nearly twice as likely as whites to have diabetes mellitus (sugar diabetes). There are two types of diabetes, Type I and Type II. Type I diabetes has not been linked to pancreatic cancer. However, Type II diabetes, which tends to occur in adults, has been shown to double the risk of pancreatic cancer. Type II diabetes is associated with obesity and lack of exercise. Diabetes can sometimes be caused by pancreatic cancer.

Pancreatitis: Pancreatitis is an inflammatory disease of the pancreas. Pancreatitis may either be acute (sudden and severe) or chronic (long-standing). Individuals that have had repeated attacks of acute pancreatitis can develop chronic pancreatitis. The risk of pancreatic cancer is elevated in all patients with pancreatitis and African Americans are at the highest risk of developing pancreatitis of any racial group.

Genetic susceptibility: The risk of pancreatic cancer due to inherited genetics in African Americans has not been well studied. However, we are developing studies to address this important unmet need. However, the currently National Comprehensive Cancer Center Guidelines recomment genetic consultation for all pancreatic cancer patients, regardless of race/enthnicity. For more information on the genetic basis of pancreatic cancer, click here.

In addition to these internal Johns Hopkins studies, we are an active participant in many collaborative studies, including:

» Click here to learn more about additional pancreatic cancer research studies at Hopkins.

» Click here to learn more about the history of the NFPTR.