When we think about the causes of cancer, gene mutations usually come to mind. But mutations are not the only culprits in cancer. Scientists now know that gene expression — whether a gene turns on or stays silent — is directed by chemicals that latch onto genes. These chemical alterations are referred to as "epigenetic" changes because — unlike mutations — they don’t alter the gene's DNA structure. Instead, the epigenetic "marks" on genes control whether a gene is turned on or not.
One common epigenetic change occurs when bulky chemical units called methyl groups (chemical formula CH3) latch onto genes. This is called methylation, and it generally prevents a gene from being turned on.
"Methylation is a normal way of regulating genes in the cell," says Amit Verma, M.B.B.S., above left, associate professor of medicine and of developmental and molecular biology. "But it sometimes occurs inappropriately, turning off genes that suppress cell growth and division. When that happens, cancer can result."
To study methylation, Dr. Verma needed a technique for scanning genes, looking for methyl groups — which is why he turned to John Greally, M.B., B.Ch., Ph.D., associate professor of genetics, for HELP.
HELP (which stands for Hpa II tiny fragment Enrichment by Ligation-mediated PCR) is a technique developed by Dr. Greally that allows investigators to evaluate the methylation status of all 25,000 human genes. "Even though a gene may appear perfectly normal, with no mutations, its abnormal methylation pattern may tip us off to its role in causing cancer," says Dr. Greally, who is also Einstein's Faculty Scholar for Epigenomics, an endowed academic position established by Dr. Ruth L. Gottesman, chairperson of the Einstein Board of Overseers, and her husband, David S. Gottesman.
The good news: While correcting a DNA mutation is extremely difficult, methyl groups and other epigenetic marks are readily reversible. Fixing the aberrant chemical marks associated with cancer could lead to effective treatments or even cures. Einstein researchers are using HELP to pinpoint epigenetic changes involved in several types of cancer.
This group of blood conditions is sometimes referred to as "pre-leukemia" because about one-third of patients develop acute myeloid leukemia after a myelodysplastic syndrome (MDS) diagnosis.
The Food and Drug Administration has approved two methylation-blocking drugs for treating MDS. "Unfortunately, only about one in three MDS patients responds to the drugs,” says Dr. Verma. “Now, using Dr. Greally's HELP assay, we're identifying the epigenetic patterns in MDS patients who respond or don't respond. Then treatment can be targeted to those patients most likely to respond."
The Albert Einstein Cancer Center (AECC) is a National Institutes of Health–designated Myelodysplastic Syndromes Center of Excellence and serves as a national referral center for people with this disorder. "Our patients have access to more advanced therapies than are provided in the practice community," says Dr. Verma. Einstein's MDS research is supported by the NIH, the AECC and private donors. (See pages 3 and 4.)
Mantle cell lymphoma
Mantle cell lymphoma (MCL) is a rare but often fatal cancer. Einstein scientists led by Samir Parekh, M.D., assistant professor in the department of medicine (oncology), have identified clusters of genes in MCL cells with too much or too little methylation. Dr. Parekh and colleagues have shown that epigenetic drug combinations can reactivate tumor-suppressor genes in MCL cells. Such drug combinations might one day be used in addition to chemotherapies now in use against MCL.
Cancer doesn't develop overnight. The process often involves dozens of mutations and epigenetic changes that occur over many years. Dr. Verma is using HELP to track the epigenetic changes that occur when a condition known as Barrett’s esophagus (caused mainly by the acid reflux of chronic, severe heartburn) develops into often-fatal esophageal cancer.
"He's dealing with the evolution of this cancer in the same way that developmental biologists deal with the development of an organism," says Dr. Greally. "In an animal, you might go from a tadpole to a frog. In this cancer you go from inflammation through different stages until you get to a deadly cancer. We hope the pattern of epigenetic marks will tell us which patients with Barrett's esophagus might be most at risk for developing esophageal cancer so that early treatment can be initiated."