Shortening Chromosomes Cause for Earlier Cancer Onset in Families with Rare Syndrome
February 15, 2007
PHILADELPHIA -- In families with a high incidence of Li-Fraumeni syndrome, the ends of individuals' chromosomes act somewhat like a lit fuse, according to researchers at The Hospital for Sick Children in Toronto. Their findings detail how telomeres, the ends of the chromosomes, shorten with every successive generation, leading to more severe cancers at an earlier age.
Their results, published in the February 15 issue of the journal Cancer Research, could represent the first biological marker for clinical monitoring in families with Li-Fraumeni syndrome, and could shed light on the important area of aging in cancer research.
"We have known since 1990 that Li-Fraumeni was associated with inheritance of a mutated form of the p53 tumor suppressor gene, but we also noticed each generation developed cancer earlier than the preceding generation," said David Malkin, M.D., the study's principal investigator, and co-director of the Cancer Genetics Program at The Hospital for Sick Children at the University of Toronto. "By studying blood samples taken from families in which members have Li-Fraumeni, we have discovered that telomeres become shorter in each generation of disease carriers, leading to a genetic instability that primes them for progressively earlier cancers."
First discovered in 1969, Li-Fraumeni syndrome is an inherited disorder that causes a wide spectrum of cancers, including breast, brain, bone and soft tissue cancers. To develop the disorder, a child only needs to receive one mutated p53 gene from one parent. Typically, the disease causes cancers relatively early in life and can strike numerous times, in differing forms, throughout a patient's life. According to Malkin, the disease afflicts between one in 10,000 to 40,000 people, but the exact number cannot be accurately determined since the random nature of the cancers makes accurate diagnosis of Li-Fraumeni difficult.
A major mystery of the disease, according to Malkin, is how certain family members could develop cancer at different times, even though they all carried the identical p53 gene mutation. Malkin and his colleagues speculated that telomere attrition -- or the successive shortening of telomeres with each normal cell division -- could account for such genomic instability, a finding confirmed by their study of 45 members from nine families with Li-Fraumeni syndrome.
"We were able to look at the DNA of multiple members of families that carried Li-Fraumeni and, overwhelmingly, telomere length was shorter in children with cancer than in unaffected siblings or parents," Malkin said. "Children whose telomeres were shorter than their parents who had the disease typically began developing cancer at a much earlier age than their parents."
Telomeres are repeated sequences of DNA at the tips of every chromosome that function as a sort of genetic slack. As cells grow and divide throughout life, the chromosomes, which contain all of an individual's genetic information, replicate as well. The enzymes that create copies of chromosomes cannot, however, physically reach the very end of the chromosome, so they leave a minute bit of this telomere slack behind each time. This is known to researchers as the "end replication problem" and has made telomeres an important subject of research in the science of aging and cancer. While Malkin and his colleagues link telomeres to genetic instability and cancer in the context of Li-Fraumeni syndrome, other researchers have studied whether it might be possible to kill rapidly growing tumors by accelerating telomere attrition.
"The discovery of telomere attrition in Li-Fraumeni really highlights the role that telomeres may perform in other cancers as well," said Malkin. "For Li-Fraumeni families, this might provide a means of determining if a child should be screened for cancer."
According to Malkin, this discovery is only one step in the further understanding of how these inherited cancers develop. Further studies are needed to find the molecular mechanisms that link p53 mutations with telomere attrition.
Funding for this research was provided by the National Cancer Institute of Canada through the Canadian Cancer Society, and the SickKids Foundation.
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