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Sifting Through "Junk" for Colorectal Cancer Clues

Cancer Center researchers find gene-regulating activity in the non-protein part of DNA.

Two Cancer Center researchers at the Geisel School of Medicine at Dartmouth have helped to identify switches that can turn on or off genes associated with colorectal cancer.

Focus article photo

Richard Cowper-Sallari, left, a graduate student in the lab of Jason Moore, PhD, right, helped identify genetic switches in cells associated with colorectal cancer.

The finding offers clues about the development of colorectal cancer and could—potentially—provide targets for new therapies. Jason Moore, PhD, a Third Century Professor of genetics, director of the Institute for Quantitative Biomedical Sciences, and associate director for bioinformatics at Dartmouth-Hitchcock Norris Cotton Cancer Center, and Richard Cowper-Sallari, a graduate student in Moore's lab, were part of a team that included researchers from Case Western Reserve University and the Cleveland Clinic. The team published its findings in Science Express, the online prepublication site for the journal Science, on April 12.

Many studies of cancer and other diseases have looked for genetic variations that lead to disease. But for this study, Moore, Cowper-Sallari, and their colleagues examined sections of DNA that do not code for proteins—sections that have sometimes been referred to as "junk" DNA. Long overlooked, junk DNA has gained more attention of late as it has become clear that it can regulate the expression of genes.

Different Codes for Cancerous and non-Cancerous Tissue
Junk DNA

This graphic representation developed by Cowper-Sallari shows what a genome looks like between the genes – in the space inhabited by so-called "junk" DNA.

"We're now starting to assign function to what historically has been known as the junk DNA—stuff in between genes that we weren't really sure what it did, if it did anything at all," Moore says. Proteins that bind to noncoding sections far away from a gene, Moore explains, can help turn that gene on or off.

The researchers looked at specific sections of noncoding DNA in nine colorectal cancer samples and three samples of healthy colon tissue. They found patterns in the sections of noncoding DNA that differed depending on whether the tissue was cancerous or healthy. They refer to these sections as variant enhancer loci (VELs). Cowper-Sallari says that the patterns they found are more reliable indicators of the presence of colorectal cancer than any currently known patterns of gene expression. "You get a very crisp signal," he says. The tumor samples were taken from patients at various stages of disease, adding to the strength of the finding.

Moore, who is also a member of the Cancer Epidemiology and Chemoprevention Research Program at the Cancer Center, adds that what he and Cowper-Sallari added to the study was their ability to make sense of mountains of data by developing computer programs and algorithms.

"An Exciting Time in Cancer Research"

"It's an exciting time in cancer research because we can now sequence entire human genomes and measure the genome on a massive scale, but what's lagging behind are the computational methods—the software, the algorithms, the statistical approaches—to allow us to make sense of this vast amount of information," Moore says. "The DNA sequencing technology to generate the data is moving a lot faster than the computational methods for making sense of it."

Cowper-Sallari adds that the intense computation required to do the analysis was only possible because of access to Discovery—Dartmouth's supercomputing cluster.

The Ultimate Cancer Research Goal

There are a number of directions the research could go in the future. Cowper-Sallari says that if they are able to look at additional samples and find the same patterns, then "the genes that are the targets of these VELs are going to be really good potential therapeutic targets for colorectal cancer."

"That's the ultimate goal—to develop drugs," Moore says. "If we can understand the biology of how these genes are turned on and off in cancer, then we can develop drugs to target them and turn them on or off."

May is National Cancer Research Month, spotlighting the importance of research in solving cancer. Find out more at www.aacr.org/ncrm.

Article by Amos Esty, originally published on the Dartmouth Now website.

May 17, 2012