About Familial Pancreatic Cancer

BRCA2 was the second familial breast cancer gene identified. It was discovered in 1995 because of a remarkable advance made by the Hopkins team studying pancreatic cancer. The team at Hopkins had discovered a "homozygous deletion" (a missing piece of DNA) in a pancreatic cancer and postulated that this missing piece of DNA is where the BRCA2 gene could be found (Schutte et al, Proceedings of the National Academy of Sciences, 1995). Indeed it was! A little known fact- the breast cancer gene BRCA2 was first found in a pancreatic cancer. Subsequently, Dr. Goggins at Hopkins demonstrated that as many as 10% of pancreas cancers are caused by inherited defects in the BRCA2 gene. One particular defect in BRCA2 (a mutation called 6174 del T) is found in about 1% of individuals of Ashkenazi Jewish descent. This mutation may explain the higher rate of pancreatic cancer observed in Jews as compared to Catholics and Protestants. Clinical testing is now available for BRCA2 gene mutations.

BRCA1 is the first breast cancer gene that was discovered. Like BRCA2, calling BRCA1 a "breast cancer gene" is a little bit of a misnomer, because it increases the risk of other cancer types as well. In fact, inherited mutations in the BRCA1 gene also increase the risk of developing pancreatic cancer. Individuals with a family history of pancreatic cancer, especially if there is also a family history of breast cancer, may wish to consider genetic testing for an inherited BRCA1 mutation. Of note, when testing is done, the lab typically will test for both BRCA1 and for BRCA2 mutations.

The PALB2 gene's official name is "partner and localizer of BRCA2". This gene contains the information to make the PALB2 protein. This protein works together with the BRCA2 protein to repair damaged DNA. The PALB2 protein is believed to stabilize the BRCA2 protein, allowing the BRCA2 protein to repair damaged DNA. We have recently found that about 3% of patients with familial pancreatic cancer have inherited mutations in the PALB2 gene. At this time, the lifetime risk of pancreatic cancer among individuals who inherit a PALB2 gene mutation is unclear, but studies are underway to better understand the risk of pancreatic cancer associated with mutations in this gene. Mutations in the PALB2 gene have also been associated with an increased risk of breast cancer. Clinical testing for PABL2 is currently available as part of most hereditary cancer panel tests.

This is a very rare hereditary syndrome in which affected family members develop polyps in their small intestines and pigmented spots on their lips and inside of their mouth. These polyps are masses of tissue that protrude from the normal inside surface of the intestine. Peutz-Jeghers is caused by inherited mutations in the STK11 gene. Patients with Peutz-Jeghers syndrome have a dramatically increased risk of developing pancreas cancer. About 35% of individuals with the Peutz-Jeghers syndrome develop pancreatic cancer by the age 60. Fortunately, mutations in the STK11 gene are very rare and account for less than 1% of familial pancreatic cancer. Clinical testing for STK11 is available.

The Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome is a rare hereditary syndrome in which affected family members develop skin moles (nevi) and melanomas (an aggressive form of skin cancer). These patients also have an increased risk of developing pancreas cancer. FAMMM is caused by inherited mutations in the p16/CDKN2A gene. This gene contains the sequence for two proteins, p16 and p14arf. Inherited mutations in the p16 protein are associated with an increased risk of pancreatic cancer and melanoma. Individuals with inherited mutations in the p16/CDKN2A gene have a very high risk of melanoma and often come from families in which several individuals have developed melanoma. Individuals with inherited mutations in the p16/CDKN2A gene also have a 15-35% lifetime risk of developing pancreatic cancer. Mutations in the p16/CDKN2A gene are very rare and are thought to account for less than 1% of familial pancreatic cancer. Clinical testing for the p16/CDKN2A gene is available as part of most hereditary cancer panels.

The Hereditary Non-polyposis Colorectal Cancer (HNPCC) syndrome, also known as "Lynch syndrome," strikes as many as 1 in 200 individuals and it is characterized by the inherited predisposition to develop colon cancer, endometrial (uterine) cancer, stomach cancer and ovarian cancer. Patients with HNPCC also have an increased risk of developing pancreas cancer. Indeed, the DNA finding typical of HNPCC, called "microsatellite instability" has recently been reported in a small (about 4%) fraction of pancreas cancers. Gene testing for HNPCC is now available.

This rare disease is characterized by the development of recurrent episodes of severe chronic pancreatitis (inflammation of the pancreas) starting at a very early age (often in patients in their teens). One of the genes responsible for hereditary pancreatitis, called the trypsinogen gene, was discovered by Dr. Whitcomb of the University of Pittsburgh.

Individuals with hereditary pancreatitis are at a very high-risk of developing pancreatic cancer, about 40% in their lifetime. Mutations in these gene are extremely rare and account for <1/2% of familial pancreatic cancer. Clinical gene testing for hereditary pancreatitis is now available.

The team at Johns Hopkins discovered that inherited mutations in the ATM gene also increase the risk of pancreatic cancer. Severe inherited mutations in ATM (when both copies of the gene are defective) are known to cause the clinical syndrome of "ataxia telangiectasia," and 2-3% of people with familial pancreatic cancer inherited a single defective (mutant) copy of the ATM gene. ATM is a gene that has an important role coordinating DNA damage repair. ATM is also involved in preventing tumor development. ATM mutations are found in 1-5% of patients with pancreatic cancer. Clinical testing for ATM is currently available as part of most hereditary cancer panel tests.