Alternative Lengthening of Telomeres in Pancreatic Neuroendocrine Tumors

The two most common tumors to arise in the pancreas, ductal adenocarcinoma and neuroendocrine tumors, couldn’t be more different.  Ductal adeocarcinomas tend to be fast-growing cancers that spread (metastasize) widely.  By contrast, pancreatic neuroendocrine tumors (PanNETs) are slow growing.  As a result, the five-year survival rate for patients with a ductal adenocarcinoma is only 5%, while it is over 65% for patients with a PanNET.  For years it was unclear why two tumors arising in the same organ behave so differently.

In the March 2011 issue of the journal Science, Y. Jiao and C. Shi at Johns Hopkins reported that when they sequenced the DNA in PanNETs they found that the genes mutated (changed) in PanNETs are completely different from the genes mutated in ductal adenocarcinomas.  The genes TP53, KRAS, p16 and SMAD4 are targeted in ductal adenocarcinomas, while the genes MEN-1, DAXX, ATRX, PTEN and TSC2 are mutated in PanNETs.  This provided the first clue that the clinical differences observed in these two tumors may have their roots in the genetic (DNA) changes in these tumors.

Recently, in the    June 30th, 2011 on-line edition of the journal Science, Christopher Heaphy, Roeland De Wilde and Yuchen Jiao in the laboratory of Alan Meeker in the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins reported that they have discovered that pancreatic neuroendocrine tumors also have unique chromosome changes called “Alternative Lengthening of Telomeres.” Alternative Lengthening of Telomeres affects the ends of chromosomes, the part of the chromosomes called telomeres. The team then showed that Alternative Lengthening of Telomeres in pancreatic neuroendocrine tumors (also known as “islet cell tumors”) is likely caused by mutations (DNA changes) in two specific genes- the DAXX and ATRX genes. This finding is important because it uncovers an entirely new cancer pathway, and it helps define the fundamental differences between ductal adenocarcinoma and neuroendocrine tumors.  Now that this new pathway has been discovered, the team hopes that this pathway can be exploited diagnostically and therapeutically.

Dr. Hruban

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