'Smothered' genes combine with mutations to yield poor outcome in cancer patients

Johns Hopkins Kimmel Cancer Center researchers have identified a set ofgenes in breast and colon cancers with a deadly combination oftraditional mutations and "smothered" gene activity that may resultin poor outcomes for patients.

The Hopkins team showed that this smothering process, called epigeneticinactivation, contributes to the aggressiveness of breast and coloncancer by disrupting biochemical pathways that normally suppress therunaway growth of cells that is the hallmark of cancer. While mutationsalter pathways by rewriting the gene's DNA code, epigenetic marksaffect genes without changing the code itself.

"Until studies like ours, it was easy to think that if we didn'tfind gene mutations in certain biochemical pathways linked to breast orcolon cancer, then those pathways were normal in such patients," saysStephen Baylin, M.D., the Virginia and D.K. Ludwig Professor for CancerResearch and deputy director of the Kimmel Cancer Center. "Now weknow that, in some patients, the pathways involved with newly discoveredmutated genes are often more frequently disrupted by epigeneticmechanisms rather than genetic ones."

"That's a powerful insight that could help us diagnose patientsquicker, predict the course of their cancer more accurately and in thefuture treat the disease more effectively," adds Baylin. A report onthis work appeared May 27 in PLoS Medicine.

The team made their discovery using microarray technology - specialsilicon chips carrying pieces of genetic material that allow thousandsof genes to be analyzed at one time. For this study, microarrays weretailored to locate cancer-related genes inactivated by an epigeneticprocess called DNA methylation. This methylation involves the bindingof molecules called methyl groups to elements of DNA called cytosinesthat are located in a gene's "on-off switch." Excess methylationsmothers the gene with too many methyl groups and interferes with thegene's normal protein production, setting the stage for a lethalcancer.

Some 189 mutated genes in breast and colon cancers, previouslyidentified by a Kimmel Cancer Center research team, were screened formethylation by Baylin's group. They found 36 genes that wereinfrequently mutated in cancer, but were "hyper"methylated, often inboth breast and colon cancers. After reviewing samples from 30 breastand 20 colorectal cancer patients as well as information from publicmicroarray databases, the researchers found 18 of these genes that werestrongly linked to poor outcome of patients with tumors carrying thesechanges.

For most of the genes, the researchers were able to reverse theirepigenetic change and reactivate them in test tubes by stripping offexcess methyl groups. This suggests that new treatments designed toreverse hypermethylation could be a simpler and more practical approachto treating cancer than strategies that attempt to replace, deactivateor compensate for mutated genes, according to Baylin.

Baylin also believes that the methlylated genes identified in thisstudy could be inactivated in a broader range of cancers as well. Thatmeans the current findings could be extended to other cancers, improvingthe ability of physicians to predict the course of additional types oftumors, he says.

"We've learned from this study that we must include both geneticand epigenetic changes when we do future microarray analyses to increaseour understanding of the genetic basis of cancer," Baylin says."Such information will provide new details about why cancers startand help us identify which cancers will be particularly aggressive inour patients."

Source: Johns Hopkins Medical Institutions