Research At Johns Hopkins University

Research into Gallbladder and Bile Duct Cancer

Experimental Research

It has become apparent over the past decade that cancer is, in essence, a genetic disease. Cancer results from an accumulation of changes in the DNA of a specific cell, giving that cell the ability to grow uncontrollably and spread. It is hoped that the study of the genetic alterations associated with biliary tract cancers will serve many purposes. First, this knowledge may help us choose better conventional chemotherapeutic agents that will be more effective against these tumors. If we learn what makes these cells grow, we should be better able to choose drugs that block this process. Second, knowledge of these genetic changes might eventually allow for these tumors to be treated by reinsertion of normal DNA into the cells ("gene therapy"). For example, if a gene which normally blocks cell proliferation is mutated and nonfunctional in these tumors, restoration of a normal copy of this gene might induce the cell to stop growing and eliminate its malignant potential. Third, it may be possible to use our knowledge of these genetic alterations to design diagnostic tests that are more sensitive and specific than the conventional means of diagnosis outlined above. This would allow potentially lethal tumors to be caught earlier when they can be cured by surgery.

Significant progress has been made at Johns Hopkins in these areas. A recent study published in Clinical Cancer Research examined the utility of detecting mutations in the K-ras gene in biliary brush cytology specimens for the diagnosis of bile duct carcinomas. The K-ras gene codes for a growth factor that has been shown to be mutated in the majority of bile duct cancers. The mutations are thought to confer a growth advantage to the cells affected. The study showed that the mutations in this gene could be detected in the same specimens collected for conventional cytology, using highly sensitive polymerase chain reaction (PCR) technology. [PCR is a laboratory technique that allows researchers to take a very small sample of DNA and amplify (copy) the sample exponentially. The result of the PCR is a sample large enough to study by genetic testing.] The sensitivity of the genetic test proved to be in fact greater than that of conventional cytology in this series (42% versus 36%), and used together the sensitivity of the combined tests rose to 62%. These results support the idea that genetic tests will soon play a major role in the diagnosis of biliary tract cancer.

Another recent study, published in Genes, Chromosomes, and Cancer, analyzed the overall genetic composition of distal bile duct cancers using two complimentary techniques. The first, conventional cytogenetics, is performed on fresh tumors, and requires intact dividing cells ("metaphases"). The second technique, comparative genomic hybridization, can be performed on frozen, non-dividing tumor cells and compares the chomosome content of the tumor with that of a normal cell. Both techniques allow gross gains and losses of genetic material to be detected. The analysis of bile duct tumors revealed frequent loss of genetic material on the long arms of chromosomes 18, 6, and 12 (18q, 6q, and 12q), and the short arms of chromosomes 10, 8, and 17 (10p, 8p, and 17p). Of great interest is the fact that many of these changes are similar to those previously identified in pancreatic cancers, suggesting that these two tumors share a number of genetic changes. Some of the sites identified suggest specific genes that might be involved in bile duct cancers. For example, the p53 gene is located on chromosome 17p and is known to be mutated in the majority of pancreatic cancers. Several small studies have strongly suggested that p53 is involved in bile duct cancers, and the frequent deletion of 17p in this study supports this notion. We are currently working to confirm this hypothesis, and identify the other genes involved.

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Clinical Research