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The Genetics of Pancreatic Cancer

-- The Discoveries

 

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Various Chromosomes:
1p, 3p, 6p & q, 8p, 10q, 12q, 13q, 18p, 21q, 22q

A roadmap to future discoveries.  The allelotype showed us a large number of chromosomal sites that are deleted in pancreatic cancer.  Some of these are known to have mutant genes.  For example, the deletions of 17p (the short arm of chromosome 17) help to inactivate the p53 and MKK4 genes that reside there.  The p16 gene is on 9p, the DPC4 gene on 18q.  But there are other chromosomal arms which are not deleted quite so universally, but for which losses have been seen in 40-60% of pancreatic cancers. These sites are listed above, and are also suspected of harboring tumor-suppressor genes. Because of the large number of these sites, it is likely that they play an important role in determining the tumor's aggressive behavior. Some are described in more detail:

1p  A region of the short arm of chromosome 1 is lost in nearly 50% of the cancers. The p18 gene, which encodes a cyclin-dependent kinase inhibitor highly similar to p16, is located in this region of 1p, but is not mutated in the cancers; thus, the tumor-suppressor gene on 1p remains unknown.

8p  A region of the short arm of chromosome 8 is lost in nearly 50% of the cancers. In one region of this chromosome, a cell line is known that has deletions of both copies, but it is not yet clear that there is a tumor-suppressor gene located there.

18p   The losses of 18p probably occur because of the loss of an entire copy of chromosome 18, including both the short (p) and long (q) arms. Since the laboratory has identified a major tumor-suppressor gene (DPC4) on the q arm, they view the loss of the p arm as a "passenger mutation", innocently carried along by the losses which inactivate one or more genes on 18q. Both copies of the DCC gene is deleted in a few pancreatic cancers, but DCC is a such a large gene that it is difficult to study.

22q  A tumor-suppressor gene termed Schwannomin (SCH) is located on chromosome 22q, and is mutated in neurofibromatosis type 2. They found no mutations of SCH in pancreatic cancer. Again, another tumor-suppressor gene probably lies on the chromosome and is waiting to be discovered.