Cancer Genetics(part 1)

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PALLADIN AND THE SPREAD OF CANCER

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Pancreatic cancer is among the most serious of all cancers.
Although only the eleventh most common form
of cancer, with about 43,000 new cases each year in the
United States, pancreatic cancer is the fourth leading cause
of death due to cancer, killing more than 36,000 people
each year. Most people with pancreatic cancer survive
less than 6 months after the cancer is 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 disease is advanced and the cancer 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 pancreatic cancer’s aggressive nature. Geneticists at the University
of Washington in Seattle had 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.
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 palladin 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 cells with normal palladin, demonstrating that the
palladin gene contributes to the ability of pancreatic cancer cells to spread.
The discovery of palladin’s link to pancreatic cancer
illustrates the power of modern molecular genetics for
unraveling the biological nature of cancer. In this chapter,
we examine the genetic nature of cancer, a peculiar disease
that is fundamentally genetic but is often not inherited. We
begin by considering the nature of cancer and how multiple
genetic alterations are required to transform a normal cell
into a cancerous one. We then consider some of the types
of genes that contribute to cancer, including oncogenes
and tumor-suppressor genes, genes that control the cell
cycle, genes in signal-transduction pathways, genes encoding
DNA-repair systems and telomerase, and genes that, like
palladin, contribute to the spread of cancer. Next, we take a
look at chromosome mutations associated with cancer and
genomic instability. We examine the role that viruses play in
some cancers and epigenetic changes associated with cancer.
Finally, we take a detailed look at how specific genes contribute
to the progression of colon cancer.

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