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Pancreatic cancer is among the most serious of all cancers. With about 45,000 new cases each year in the United States, it is only the tenth most-common form of the disease, but it is the fourth leading cause of death due to cancer, killing more than 38,000 people each year. Most people with pancreatic cancer survive less than 6 months after they are diagnosed; only 5% survive more than 5 years. A primary reason for pancreatic cancer’s lethality is its propensity to spread rapidly to the lymph nodes and other organs. Most symptoms don’t appear until the cancer is advanced and has invaded other organs. So what makes pancreatic cancer so likely to spread?

In 2006, researchers identified a key gene that contributes to the development of pancreatic cancer—an important source of insight into the disease’s aggressive nature. Geneticists at the University of Washington in Seattle found a unique family in which nine members over three generations were diagnosed with pancreatic cancer (Figure 23.1). Nine additional family members had precancerous growths that were likely to develop into pancreatic cancer. In this family, pancreatic cancer was inherited as an autosomal dominant trait.

By using gene-mapping techniques, the geneticists determined that the gene causing pancreatic cancer in the family was located within a region on the long arm of chromosome 4. Unfortunately, this region encompasses 16 million base pairs and includes 250 genes.

To determine which of the 250 genes in the delineated region might be responsible for cancer in the family, researchers designed a unique microarray (see Chapter 20) that contained sequences from the region. They used this microarray to examine gene expression in pancreatic tumors and precancerous growths in family members, as well as in sporadic pancreatic tumors in other people and in normal pancreatic tissue from unaffected people. The researchers reasoned that the cancer gene might be overexpressed or underexpressed in the tumors relative to normal tissue. Data from the microarray revealed that the most-overexpressed gene in the pancreatic tumors and precancerous growths was a gene encoding a critical component of the cytoskeleton—a gene called palladin. Sequencing demonstrated that all members of the family with pancreatic cancer had an identical mutation in exon 2 of the palladin gene.

The palladin gene is named for Renaissance architect Andrea Palladio because it plays a central role in the architecture of the cell. Palladin protein functions as a scaffold for the binding of the other cytoskeleton proteins that are necessary for maintaining cell shape, movement, and differentiation. The ability of a cancer cell to spread is directly related to its cytoskeleton; cells that spread typically have poor cytoskeleton architecture, enabling them to detach easily from a primary tumor mass and migrate through other tissues. To determine whether mutations in the palladin gene affect cell mobility, researchers genetically engineered cells with a mutant copy of the palladin gene and tested the ability of these cells to migrate. The cells with mutated palladin were 33% more efficient at migrating than were cells with normal palladin, demonstrating that the palladin gene contributes to pancreatic cancer cells’ ability to spread.

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