A Look at Familial Pancreatic Cancer
By Kathleen Murphy, PhD

Cancer of the pancreas is the fifth leading cause of cancer death. This year it is estimated that 28,000 Americans will be diagnosed with pancreatic cancer and about 28,000 will die from it. The deadly nature of this disease has focused efforts to identify individuals at risk with the hope that early detection will lead to improved clinical outcome.
Although the majority of pancreatic cancer cases are sporadic (non-hereditary), up to 10% of cases appear to be caused by inherited genetic factors. The existence of families with multiple members affected with pancreatic cancer has long been noted. Indeed, 5 to 10% of all people with pancreatic cancer have a first-degree relative with the disease. The question still remains, however, whether the aggregation of pancreatic cancer in these families was truly due to a genetic predisposition, a shared environmental exposure such as cigarette smoking, or simply due to chance. Recent studies have indicated that even after adjusting for environmental risk factors, pancreatic cancer does aggregate within some families. These findings strongly suggested the existence of an inherited genetic component to the disease.
In the last decade, advances in pancreatic cancer research have lead to a significantly increased understanding of the genetics of the disease. It is now clear that pancreatic cancer, like other forms of cancer, is the result of multiple genetic changes (mutations). These mutations can be either inherited or acquired. Several acquired gene mutations have been identified in sporadic pancreatic cancer. These include mutations in the oncogene, k-ras, and tumor suppressor genes, p53 and p16. However, there is still much to be learned about the familial nature of pancreatic cancer.
Researchers have identified several genes that appear to play a role in the familial aggregation of pancreatic cancer. At least five genetic syndromes are known to cause an increased occurrence of pancreatic cancer in families. These syndromes are familial breast cancer, Familial Atypical Multiple Mole-Melanoma (FAMMM), Peutz-Jeghers Syndrome, Hereditary Nonpolyposis Colorectal Cancer (HNPCC), and hereditary pancreatitis. Each of these syndromes is associated with specific inherited gene mutations (BRCA2 gene, p16 tumor suppressor gene, the STK11/LKB1 gene, DNA mismatch repair genes, the cationic trypsinogen gene, respectively). However, these syndromes do not account for the majority of hereditary pancreatic cancer since there is no clinical evidence of these syndromes in many of the families in which pancreas cancer aggregates. Thus the gene(s) responsible for much of the inherited predisposition to pancreatic cancer remain to be identified.
In 1994, to learn more about the role of inheritance in pancreatic cancer, The Johns Hopkins Medical Institutions established the National Familial Pancreas Tumor Registry (NFPTR). Entry into the registry involves completing a questionnaire and the option to donate a blood sample. (Visit the Johns Hopkins Pancreatic Cancer web site at http://pathology.jhu.edu/pancreas.) To date, more than 450 families have enrolled in this registry. A major objective of NFPTR is to identify gene mutations responsible for the inherited nature of pancreatic cancer. Samples from the registry are currently being analyzed in order to identify these mutations. Prospective analysis of the registry has already found that in kindreds with three or more affected family members there is a 57-fold increased risk of pancreatic cancer, supporting the genetic basis of the disease in these families. The project, under the direction of Drs. Scott Kern and Ralph Hruban, is still at an early stage, but preliminary results are expected within the year.
Information gained from NFPTR has immediate potential to be translated into clinical practice. Most notably, understanding the genetics of the disease may allow the development of new screening methods. Identification of high-risk patients on the basis of genetic analysis would enhance the potential for early diagnosis and may significantly improve outcome. In addition, knowledge of the genetic basis of familial pancreatic cancer may help identify important prognostic factors, influence therapeutic decision-making, and aid in the design of new therapies. Thus, understanding the genetics of pancreatic cancer will hopefully lead to improved methods of diagnosis and treatment of this deadly disease.
Dr. Kathleen Murphy is a Johns Hopkins Fellow in the Department of Pathology.
References
Goggins, M., Kern, S.E., Offerhaus, J.A., Hruban, R.H. Progress in cancer genetics: Lessons from pancreatic cancer. Ann. Oncol. 1999;10 suppl 4:4-8
Hruban, R.H., Peterson, G.M., Tersmette, A.C., Offerhaus, G.J.A., Falatko, F., Yeo, C.J., Kern, S.E. Familial pancreatic cancer. Ann Oncol. In press

Development of pancreatic cancer due to multiple genetic changes.