Jan. 13, 2009
Rules for Gene Silencing in Cancer Cells Identified
Human cancers from breast and lung have a common pattern of genes vulnerable to silencing by DNA methylation, researchers at Emory University and the Georgia Institute of Technology have found.
The results are published in the January issue of Cancer Research.
On their way to becoming tumors, cells have to somehow inactivate several "tumor suppressor" genes that usually prevent cancer formation. Methylation is a subtle punctuation-like modification of the DNA that marks genes for silencing, meaning that they are inactive and don't make RNA or proteins.
"We've developed a set of guidelines that allow us to predict which genes have an increased risk of silencing by DNA methylation," says senior author Paula Vertino, PhD, associate professor of radiation oncology at Emory University School of Medicine and Emory Winship Cancer Institute. "That vulnerability could make those genes good markers for diagnosis and risk assessment in patients."
Postdoctoral fellow Michael McCabe, PhD, was first author, with contributions from Eva Lee, associate professor of industrial and systems engineering at Georgia Tech.
The "signature" of DNA methylation found in cancer cells came from the team's previous work analyzing cell lines that artificially overproduce an enzyme which adds methylation markers to DNA. Vertino's team calls the signature PatMAn for "pattern-based methylation analysis."
PatMAn is based on seven "key words" 8-10 nucleotides long and can predict which genes become methylated in breast and lung cancers in addition to the artificial cell lines, the researchers found.
If the key words are in the DNA sequence near the promoter of the gene, it is more likely to be methylated. The promoter of a gene is the place where enzymes start making DNA into RNA.
Further analysis led to the team's realization that PatMAn overlaps with the pattern of DNA bound by a set of proteins known as the Polycomb complex in embryonic stem cells. Polycomb appears to keep genes that regulate early development turned off in embryonic stem cells.
The researchers combined PatMAn with the Polycomb binding pattern to generate SUPER-PatMAn, an improved version of PatMAn that could predict methylation-prone genes in cancers with more than 80 percent accuracy.
Vertino notes that the methylation pattern in cancer cells appears to echo Polycomb's binding in embryonic stem cells. Many of the genes affected play important roles in embryonic development.
"Many of the genes predicted by our algorithms to be methylation-prone are developmental regulators," she says. "Our findings could support the idea that methylation-mediated silencing helps to lock the developmental state of tumor cells into being more stem cell-like."
The research was funded by the National Institutes of Health, the National Science Foundation, the American Cancer Society and the Georgia Cancer Coalition.
Reference: A mutli-factorial signature of DNA sequence and Polycomb binding predicts aberrant CpG island methylation McCabe, M.T., Lee, E.K, and Vertino, P.M, Cancer Research, January 2009.
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