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The Genetics of Pancreatic Cancer

-- The Discoveries

 

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p53 Mutations

Why are p53 mutations important?  The p53 gene suffers deletions in nearly 90% of pancreatic cancers. Nearly 60-70% have a point mutation which inactivates the remaining copy of the gene.   Among the various human tumor types, p53 mutations are the most common known. p53 is thought to be a master controller of certain tumor-suppressive pathways. It binds specific sequences of DNA and directs the production of RNA from nearby genes, a process called transcriptional activation. Because all naturally-occurring p53 mutations impair p53's ability to bind DNA, this important tumor-suppressive function is lost.

Any clues to why they occur?  In comparison with other tumor types, there is a peculiar preference for pancreatic carcinomas to have intragenic deletions, and in particular 1-2 basepair microdeletions (17% versus, for example, less than 1% in colon cancer). These deletions frequently were within repeated runs of single nucleotides or nucleotide pairs. The cause is unclear, but the possibilities are intriguing, since such mutations are of the type seen with exposure to mutation-inducing chemicals. As a bit of background, it has been suggested that exposure to particular environmental or endogenous mutagens might be related to specific mutation spectra in p53. For example, aflatoxin-associated mutations in hepatocellular carcinoma very frequently involve a particular site within the p53 gene. It has also been observed that different mutations are favored in colorectal, lung or UV-induced skin carcinomas. Knowledge of the causative agents or the mechanisms of genetic alteration might provide clues to the processes involved in causing pancreatic cancers. One would hope to use this understanding to help reduce the incidence of the disease among the population.