St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project takes new approach to measuring the repetitive DNA at the end of chromosomes and opens new window on mechanisms fueling cancer
Genome sequencing data once regarded as junk is now being used to gain important clues to help understand disease. The latest example comes from the St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, where scientists have developed an approach to mine the repetitive segments of DNA at the ends of chromosomes for insights into cancer.
These segments, known as telomeres, had previously been ignored in next-generation sequencing efforts. That is because their repetitive nature meant that the resulting information had defied analysis and the data were labeled as junk. But researchers have now traced changes in the volume of telomeric DNA to particular types of cancer and their underlying genetic mistakes. Investigators found that 32 percent of pediatric solid tumors carried extra DNA for telomeres, compared to just 4 percent of brain tumors and none of the leukemia samples studied. The findings were published recently in the journal Genome Biology.
Using this new approach, the investigators have linked changes in telomeric DNA to mutations in the ATRX gene and to longer telomeres in patients with a subtype of neuroblastoma, a cancer of the sympathetic nervous system. Telomere length limits how many times cells can divide. Mechanisms that maintain or lengthen telomeres contribute to the unchecked cell division that is a hallmark of cancer.
"This paper shows how measuring the DNA content of telomeres can enhance the value of whole- genome sequencing," said Matthew Parker, Ph.D., the paper's first author and a St. Jude postdoctoral fellow. "In the case of the ATRX mutation, the telomere findings gave us information about the mutation's impact that would have been hard to get through other means."
The results stem from the largest study yet of whole-genome sequencing to measure the content of telomeric DNA. The effort involved whole-genome sequencing of normal and tumor DNA from 235 pediatric patients battling 13 different cancers. For comparison, normal DNA from 13 adult cancer patients was included in the research.
"There's been a lot of interest among cancer researchers into telomere length," said Richard Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. "While more research remains, we think it's important to begin to characterize the genetic sequences that make up the telomeres. That's a crucial first step to understanding more precisely any role they may play in cancer."
The Pediatric Cancer Genome Project sequenced the complete normal and cancer genomes of more than 600 children and adolescents with some of the most aggressive and least understood cancers. Investigators believe the project's findings will lay the foundation for a new generation of clinical tools. Despite advances, cancer remains the leading cause of death by disease of U.S. children age 1 and older.
The human genome is stored in the four-letter chemical alphabet of DNA, a molecule that stretches more than 3 billion characters in length and provides the instructions for building and sustaining life. Those instructions are the genes that are organized into the 46 chromosomes found in almost every cell.
Each chromosome ends with the same six-letter DNA sequence that is associated exclusively with telomeres. The DNA sequence does not vary, but the number of times it is repeated does, affecting the length of the telomeres. Telomeres shorten each time cells divide, which explains why their length declines naturally with age.