Gene Mutations Linked to Altered Telomeres in Cancer Cells - July 12, 2011 • Volume 8 / Number 14

Gene Mutations Linked to Altered Telomeres in Cancer Cells
July 12, 2011 • Volume 8 / Number 14

Researchers have identified an association between mutations in two genes and highly abnormal telomeres in multiple forms of cancer, including the most common and aggressive form of malignant brain tumor, glioblastoma multiforme (GBM). Among hundreds of tumors tested, those with mutations in either of the two genes also had abnormal telomeres, researchers at the Sol Goldman Pancreatic Cancer Research Center and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins reported online June 30 in Science.

The researchers can now investigate whether the mutations contribute directly to changes in telomeres and cancer, which could have clinical implications. The work builds on a recent genetic analysis of pancreatic neuroendocrine tumors (PNET), a type of pancreatic cancer, by Hopkins researchers. This prior study found frequent mutations in one of two genes involved in the packaging of DNA—DAXX and ATRX.

The proteins encoded by these genes modify chromosome structure and are active at the telomeres. In the new study, the researchers hypothesize that the inactivation of these genes may make it possible for cancer cells to lengthen their telomeres, ensuring their survival. Normally, telomere DNA is progressively lost as a cell divides until the cell is no longer viable.

“The mutations in DAXX or ATRX seem to allow cancer cells to overcome the natural loss of telomere DNA and to keep dividing indefinitely,” said Dr. Alan Meeker, a molecular pathologist at the Kimmel Cancer Center and a lead author of the study. “This hypothesis needs to be tested through rigorous functional studies in the lab.”

When he and his colleagues analyzed more than 400 tumors, every sample that had mutations in the ATRX gene had abnormal telomeres. (They did not find any DAXX mutations in the non-PNET samples.) The association was relatively common in certain cancers, including central nervous system tumors, particularly GBM in children and adults.

“There was a perfect correlation between mutations in DAXX or ATRX and abnormal telomeres,” said Dr. Meeker. “This was really exciting. You rarely ever see a perfect correlation in biological research.” Understanding the mechanisms involved in generating the abnormal telomeres could reveal new therapeutic targets for cancer, he added.
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http://www.cancer.gov/ncicancerbulletin/071211/page3