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The Genetics of Pancreatic Cancer

-- The Discoveries

 

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DPC4 Mutations

Why did you go looking for this gene?  The nearly ubiquitous deletions (termed loss of heterozygosity, or LOH) of chromosome 18q suggested the inactivation of a very important tumor-suppressor gene which resides there, the identity of which was unknown at the time. 18q is one of the most frequently deleted chromosomal arms among a variety of human cancer types. A candidate gene on 18q, the DCC gene, had not been reported to be mutated in pancreatic cancer. Thus, for years, the search continued for the elusive gene.

How did you find it?  The laboratory decided to scan the suspected area with multiple markers, in order to evaluate the integrity of the chromosome. In one small area (about 1% of the length of the chromosome, in the region termed 18q21.1), they found multiple small deletions of a type which were previously thought to be quite rare. These were deletions which affected both normal copies of the chromosome, termed "homozygous deletions", and they were found in 30% of the cancers. A gene was cloned from this region. Because this was the fourth locus to be investigated for this special form of deletion in pancreatic cancer, they named the gene DPC4 (for Deleted in Pancreatic Cancer, locus 4). In a number of cases which did not have these homozygous deletions, other forms of mutations were found which would inactivate this gene. In all, 50% of pancreatic cancers, as well as lesser proportions of other cancers (such as bladder, breast, lung, bile duct, and colon tumors), experience a total inactivation of the DPC4 gene due to mutations. The gene is suspected of normally acting to prevent the occurrence of tumors of the pancreas and other organs, and so is one of a small number of known tumor-suppressor genes.

Dpc4.jpg (1265956 bytes)

Location of DPC4 on chromosome
18 near the DCC gene

What does DPC4 do?  A fascinating clue to the biochemical function of this protein was suggested by an Internet-based computer search of DNA databases. DPC4 is very similar to a gene in the fruit fly, Drosophila malanogaster, which is needed in early fly development. The signals are part of the TGF- superfamily of signaling pathways.  When we used a genetic strategy to knock out the TGF- gene in a cancer cell, we found we had also inactivated the TGF- pathway.   These pathways usually act to promote differentiation (maturation to normal adult forms) and to slow the growth of cells. Similar proteins are also found in the worm C. elegans. We have recently found that DPC4 binds to a specific sequence in DNA, allowing DPC4 to turn on the expression of certain genes.

What does TGF- do?  TGF- has a role in humans similar to that in other species, and most normal cells stop proliferating when exposed to TGF-. One of the most remarkable findings about tumor cells from any of a number of sites in the body is that the majority of them do not become suppressed by TGF-. It is therefore hoped that the finding of mutations in DPC4 will help us to understand one of the most basic abnormalities of cancers, which is their inability to respond to the body's own normal signals which should control their growth. Perhaps by finding a way to overcome this blockade to TGF- signals, we can re-establish a natural and powerful means to rein in the tragic aggressiveness of cancer.