Telomere Attrition Blamed for Early Onset Cancer

Frederick Li and Joseph Fraumeni first described Li-Fraumeni syndrome (LFS), which is caused by hereditary mutations in the chromosome 17 p53 tumor-suppressor gene. Females with LFS have an increased risk for developing breast cancer, while males and females may also be at risk for developing leukemia, melanoma, colon cancer, pancreatic cancer, brain cancer, and adrenal-corticoid tumors. These cancers often occur at younger ages than are typically observed in the general population, often before age 45. In addition, individuals with a mutation in the p53 gene have a higher risk for developing multiple primary cancers.

Investigators at The Hospital for Sick Children (Toronto, Canada; www.sickkids.ca) analyzed mean telomere length and MDM2-SNP309 polymorphism status in total of 45 peripheral blood lymphocyte samples from 9 LFS families and 15 controls. MDM2 (mouse double minute) is a gene originally identified as amplified in a malignant mouse tumor. It has since been found to be amplified in a number of human cancers including glioblastoma and some osteosarcomas. The gene product of MDM2 is an E3 ubiquitin ligase charged with controlling the levels of the transcription factor p53. Upon binding to MDM2, p53 is ubiquitylated at certain lysine residues, exported from the nucleus, and degraded by the proteasome.

The investigators reported in the February 15, 2007, issue of Cancer Research that telomere length was shorter in carriers with cancer than in healthy carriers and wild-type controls. Within each family, telomere length was shorter in children with cancer than in their healthy siblings and their non-carrier parents. Telomere attrition between children and adults was faster in carriers than in controls. Accelerated telomere attrition in LFS suggested that telomere length could explain earlier age of onset in successive generations of the same family with identical p53/MDM2-SNP309 genotypes.

"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 senior author Dr. David Malkin, professor of oncology at The Hospital for Sick Children. "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. 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, Children whose telomeres were shorter than their parents who had the disease typically began developing cancer at a much earlier age than their parents.”


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The Hospital for Sick Children