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The Case of the Mysteriously Lengthening Telomeres

Science Express, June 30, 2011

The enzyme telomerase has been linked to cancer because it aids in the ongoing cell division that is the hallmark of cancer.  Yet, some cancers manage to keep their telomeres intact without telomerase, and now researchers have uncovered important clues as to how they do it.

Telomeres have been compared to the plastic caps on the end of shoelaces because they protect the genetic material at the ends of chromosomes and help make sure DNA gets copied correctly as cells divide.   Each time a cell divides, its telomeres get shorter.  Once a cell has used up its telomeres, it permanently ceases dividing or dies, helping to prevent diseases like cancer, characterized by cells that continually divide.   The enzyme telomerase, discovered by Hopkins Professor Carol Greider, Ph.D., maintains the length of telomeres, and most cancer cells use large amounts of the enzyme to ensure their immortality.  Yet, mysteriously some cancer cells maintain their telomeres without it, but now Kimmel Cancer Center researchers have helped solve the mystery, linking mutations in two genes to this cancer cell phenomenon known as “alternative lengthening of telomeres (ALT).” 

“Finding the genes responsible for alternative lengthening of telomeres is the first step in understanding this process and provides opportunities to develop new drug therapies,” says Nickolas Papadopoulos, Ph.D.  It was his research to map the genome of pancreatic neuroendocrine tumors that led to the telomere discovery. 

 Papadopoulos and team found two genes, ATRX and DAXX, were frequently altered in these cancers.  Collaborator Ralph Hruban, M.D., aware that the genes were active in the telomere region of DNA, acted on a hunch and had 41 samples of the pancreatic neuroendocrine tumors used in the genome mapping study examined, and turned up signs of alternative lengthening of telomeres in 25 of them. 

Using special cancer imaging techniques to zero in on the telomeres, collaborators Alan Meeker, Ph.D. and Christopher Heaphy, Ph.D. found large pockets of telomere DNA indicative of ALT in the 25 samples, with each holding about 100 times more telomere DNA than normal cells.  Nineteen of these samples contained either ATRX or DAXX gene mutations, while the remaining cases showed abnormalities at the protein level.  “We saw a 100 percent correlation between abnormalities in ATRX and DAXX and alternative lengthening of telomeres,” says Meeker.   He suspects that the mutations alter the way the telomere DNA is packaged in cells, exposing those areas to instability. 

Meeker, Papadopoulos and team have since found ATRX mutations in several types of brain cancer, including pediatric and adult glioblastoma.  In the pancreas neuroendocrine tumor studies, spearheaded by Luis Diaz Jr., M.D., the mutations were linked to improved survival.  “If this correlation holds up, we could use alternative lengthening of telomeres and ATRX/DAXX mutations as a method to determine a patient’s prognosis.  We could also develop treatments that target these genes,” says Meeker.

The research was funded by the Caring for Carcinoid Foundation, the Lustgarten Foundation for Pancreatic Cancer Research, the Virginia and D.K. Ludwig Fund for Cancer Research, the National Institutes of Health,  the Sol Goldman Pancreatic Cancer Research Center, the American Cancer Society, The Pediatric Brain Tumor Foundation Institute, The Duke Comprehensive Cancer Center Core, the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, and the Department of Defense Breast Cancer Research Program.