If you are like the vast majority of Americans over age 50, you probably have not had a colonoscopy to screen for colorectal cancer. Yet if everyone in this age group were willing to undergo the admittedly unpleasant procedure once every decade, early detection could prevent 90 percent of the annual 150,000 colorectal-cancer diagnoses and 50,000 deaths from the illness.
"If diagnosed at an advanced stage, only about 5 percent of patients will survive colorectal cancer," said Dr. William Grady, an expert on the disease. "We have effective means to prevent the disease, but they aren't acceptable to most people. Compliance with screening guidelines for colorectal cancer is only about 16 to 20 percent."
Those statistics frustrate Grady, who moved his laboratory to the Clinical Research Division from Vanderbilt University Medical Center last month. So he's decided to try to change them. His mission is to develop a simple screening test for the disease that is equally as effective — but much more palatable to the public — than colonoscopy. An accurate new test that lacks the discomfort of colonoscopy, he says, could help to bump colorectal cancer from its rank as the third most deadly cancer in the United States. He believes such a test could be on the market in five to 10 years.
Colonoscopy requires clearing the colon with laxatives or enemas, then sedation and insertion of a long flexible tube into the colon to search for and remove potentially precancerous growths called polyps. The procedure carries a small but serious risk of puncturing the intestine.
Grady's lab is working to develop a safe, accurate and easy-to-administer test that picks up cancer warning signals in the DNA found in a blood or stool sample. Such a test would likely encourage more people to undergo screening. It also would limit the use of colonoscopy to those found to be at risk for cancer by the DNA test, who would then undergo the procedure to have polyps removed.
Grady's approach exemplifies the power of translational research, which aims to move discoveries of basic cancer biology out of the laboratory and into the doctor's office, said Dr. Fred Appelbaum, director of the Clinical Research Division.
"Bill is in a position not only to make important contributions in our understanding of how gastrointestinal cancers develop, but also how they can be better diagnosed and prevented," he said. "He brings a wealth of expertise to our solid-tumor program."
The opportunity to prevent some of the most deadly solid tumors, or to detect them before they are advanced and hard to cure, is what drew Grady to gastoenterology while a medical student at the University of Michigan. The specialty focuses on the health of the intestine, stomach and esophagus. As a gastroenterologist, rather than an oncologist, he primarily works with patients before they develop cancer.
"The natural anatomy of the organs of the gastrointestinal (GI) tract, as well as the available technology for studying them, offer excellent possibilities for early cancer detection and cancer prevention — more so than for most other types of cancer," Grady said.
That's because many cancers of the GI tract, particularly those in the colon or esophagus, tend to develop slowly. It takes about 10 years for a colon polyp to develop into a cancer. With endoscopes — long, flexible tubes that can be equipped with cameras and forceps — doctors can actually see inside the GI tract and remove suspicious growths. The DNA-based stool or blood test that Grady hopes to develop would identify individuals that have polyps likely to become cancerous well before they do. When colorectal cancer is caught in its earliest stage, chances for survival are about 95 percent.
To create a new test, Grady's lab will identify the earliest genetic changes that accompany a normal intestinal cell's transition to cancer. The investigators also must develop strategies to overcome the technical obstacles to detecting minute amounts of cancer-related DNA in a vast sea of normal DNA in the blood or stool.
While completing a gastroenterology fellowship with Dr. Sandy Markowitz at Case Western Reserve University in Cleveland, Grady demonstrated the feasibility of detecting rare cancer-cell DNA in the blood serum of colorectal cancer patients.
"We've been able to detect 10 to 50 picograms of cancer-specific DNA in blood serum, which is roughly equivalent to the amount found in about one to five cells," he said. "That enables us to detect roughly one cancerous DNA molecule among about 10,000 healthy DNA molecules."
That test focused on a genetic change that becomes evident in more advanced cancers. Now, Grady's lab is working to find earlier DNA-based cancer clues, which, once identified, will help doctors to prevent the disease from ever reaching an advanced and potentially incurable stage.
Although detecting cancer-specific DNA in the stool poses more technical challenges than blood because it contains DNA from ingested plant or animal matter, Grady believes that stool may be more likely to contain traces of the earliest signs of cancer. He is currently working to design a highly effective and affordable test of this kind with Exact Sciences Corporation. The company already has a stool-based screening test on the market, although it is expensive and not as sensitive as colonoscopy.
Gene methylation
The primary type of genetic abnormality Grady's group hopes to detect is called DNA methylation, in which a chemical group is tagged onto a gene. Methylation causes a gene to be turned off, or silenced. In many cancers, silencing of certain genes important for normal cell growth is linked to tumor development. Grady and others already have identified candidate genes which, when methylated, are associated with early-stage colorectal cancer. Ultimately, he hopes to develop a procedure that simultaneously checks the methylation status of multiple genes implicated in the cancer process.
Grady's lab also investigates the consequences that result when genes become methylated. The answers could lead to the development of new drugs that block methylation or the tumor-promoting effects caused by methylation, thus preventing cancer from ever developing. Several members of his lab focus their research on a protein called TGF-beta receptor type 2, a protein often found to be abnormal in colorectal-cancer patients that have methylated genes in their tumors. Scientists suspect that abnormalities in the TGF-beta receptor are one of the causes for colon polyps turning into colon cancer.
In addition to his laboratory work, Grady will devote 20 percent of his time to patient care at the Veterans Administration Puget Sound Health Care System in Seattle. He is also a member of the Gastrointestinal Cancer Prevention Program at the Seattle Cancer Care Alliance, a monthly clinic for individuals at high risk for developing gastrointestinal cancers.
Grady is enthusiastic about forging collaborations with colleagues in the Public Health Sciences Division who investigate the link between dietary factors and colorectal-cancer risk, which may in part be due to the effect of certain nutrients on DNA methylation. These and other opportunities for interaction are what drew Grady to back to Seattle, where he completed his residency at the University of Washington in 1994.
"One obvious draw of Fred Hutchinson is the institution's interest in early detection," he said. "There are also a number of investigators here interested in the basic biology of methylation as well as in the development of tumor biomarkers. The opportunities to make significant advances in gastrointestinal cancer here are outstanding."
Alliance, UW launch Gastrointestinal-Cancer Prevention Program
Not everyone can put off screening for colorectal cancer until after age 50. About 5 percent of all colorectal cancer cases are due to one of several inherited syndromes that confer an exceptionally high risk for developing the disease at an early age, said Dr. William Grady, a new investigator in the Clinical Research Division.
Those with these and other hereditary cancer syndromes may benefit from a visit to the Gastrointestinal (GI) Cancer Prevention Program, a new clinic launched this month at the Seattle Cancer Care Alliance and the University of Washington. The clinic, which meets the fourth Monday morning of each month on the fourth floor of the Alliance, is a multidisciplinary clinic for people known to be at high risk for colorectal, gastric and pancreatic cancer.
"An example of someone at high risk would be a person who has a family member who has been diagnosed with one of these cancers at an early age," said Grady, a gastroenterologist with the program. "We'll provide a risk assessment for that individual and family members, including genetic testing and counseling for known hereditary cancer syndromes. Based on results of the risk assessment, individuals will receive individualized cancer surveillance recommendations and will be offered opportunities to participate in clinical trials aimed at cancer prevention and detection."
Program health-care providers include:
* Drs. Teresa Brentnall, Gideon Steinbach and William Grady, gastroenterologists
* Dr. Elizabeth Swisher, gynecologic oncologist
* Dr. Matthew Mealiffe, medical geneticist
* Robin Bennett, genetic counselor
* Sarah Washburn and Julie Meyers, nutritionists
For more information about the Gastrointestinal Cancer Prevention Program, contact Whitney Neufeld-Kaiser, program manager, at (206) 616-5241 or whitneyn@u.washington.edu.
