First Familial Pancreatic Cancer Gene Identified
- Date:
- December 12, 2006
- Source:
- Public Library of Science
- Summary:
- At least 10 percent of pancreatic cancers are thought to be familial, i.e., caused by inherited genetic mutations. The responsible genes have so far remained elusive, but one of the research teams that had been on a pancreatic cancer gene hunt for years now reports success: Teri Brentnall (University of Washington), David Whitcomb (University of Pittsburgh), and colleagues publish the identification of the palladin gene as the one mutated in a large family they had been studying for a while.
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Pancreatic cancer is relatively rare but deadly; most patients die within a year of diagnosis, and it is the fourth leading cause of cancer deaths in the US. At least 10% of pancreatic cancers are thought to be familial, i.e., caused by inherited genetic mutations. The responsible genes have so far remained elusive, but one of the research teams that had been on a pancreatic cancer gene hunt for years now reports success: Teri Brentnall (University of Washington), David Whitcomb (University of Pittsburgh), and colleagues publish the identification of the palladin gene as the one mutated in a large family they had been studying for a while.
Family X, as it is referred to, has 18 members from 4 generations who had either pancreatic cancer or precancerous lesions of the pancreas. Tracing the DNA segments that are shared by these patients but not present in the healthy family members, the researchers had previously mapped the gene to a relatively small region of chromosome 4, which contains 243 known genes. They then made a gene chip that can measure expression levels of these 243 candidate genes and compared normal pancreas tissue with cancerous pancreas (both from a Family X member and from unrelated patients with pancreatic cancer).
Palladin, one of the 243 genes, turned out to be abnormally highly expressed in both the Family X tissue and the sporadic cancers. Named after the 16th century Italian architect Palladio, palladin codes for a component of the cytoskeleton (the scaffold that helps to control cell shape and motility). Next, the researchers quantified the expression of palladin RNA in an independent set of normal and cancerous pancreatic samples, and in precancerous pancreatic tissue taken from family X members. This analysis indicated that palladin was overexpressed early in sporadic and inherited pancreatic cancer development. Sequencing of the palladin gene then uncovered a mutation in palladin that was present in Family X members with pancreatic cancer or precancerous lesions but not in unaffected members. Finally, the researchers showed that the introduction of mutated palladin into a human cell line growing in the laboratory increased its migration rate and disrupted its cytoskeleton (both features typical of cancer cells).
These results leave little doubt that mutated palladin is involved in the development of pancreatic cancer in Family X. Moreover, they suggest that overexpression of palladin is also associated with and possibly responsible for a sizeable proportion of sporadic pancreatic cancers. The identification of palladin as a "pancreatic cancer gene" provides researchers with a molecular entry point into the cellular processes underlying this cancer and will hopefully help to improve diagnosis and development of new treatments for this deadly disease.
Citation: Pogue-Geile KL, Chen R, Bronner MP, Crnogorac-Jurcevic T, White Moyes K, et al. (2006) Palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism. PLoS Med 3(12): e516. (http://dx.doi.org/10.1371/journal.pmed.0040516)
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