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Reported by Nick Zagorski
February 23, 2005

The past decade has brought about tremendous advances in genetics and molecular biology. In a short time, we have gone from sequencing the genome of a bacterium to sequencing the genome of a human. Polymerase Chain Reaction (PCR) has enabled researchers to take a minute sample of DNA and amplify it a million-fold, and DNA evidence has become the new “fingerprints” of forensic investigations. More recently, gene microchips have made it possible to look at the activity of thousands of genes simultaneously.

Before this genomic revolution, many physicians didn’t view cancer as a molecular disease –even though cancer was known to be a result of genetic changes-- but rather, as a disease of the cell. Cancer detection focused on screenings and imaging in order to visualize early-stage tumors, and subsequent treatment, including surgery and radiation, relied on removing these uncontrollably growing cells from the body.

All of these advances in genomics have changed how scientists look at cancer, and it’s beginning to change the way physicians go about detecting, preventing, and treating this disease. "For a while now, the fields of oncology and genetics have been coming together to form a new ‘hybrid science’ known as cancer genetics," says Jeffrey Weitzel, M.D., of City of Hope, an NCI-designated Comprehensive Cancer Center. “Now we need to ride this genomic revolution all the way to the clinic."

Weitzel, who is director of City of Hope’s Department of Clinical Cancer Genetics, works on familial cancers; the small subset of cancers that develop due to genetic mutations passed by along by family members. He and his team hope to improve the recognition and assessment of all individuals who may inherit an increased risk of cancer (see SideBar story).

Weitzel, though, is just one of many NCI-supported researchers at universities and comprehensive cancer centers nationwide who have been trying to unravel the interactions of cancer and genetics. Recently, a lot of cancer research has focused in the field of epigenetics, which examines the regulation of all the genes in a cell. While human chromosomes contain somewhere between 25,000 to 30,000 genes, only a small subset of them are turned on in any given cell at any given time. This allows the cells to perform their specialized functions efficiently and only grow, move, or divide when necessary. If any external cues signal a change, then the cell quickly alters which genes are turned on or off in response to the new situation. If each gene can be considered an orchestral instrument, then epigenetics studies the conductors --the mechanisms by which a cell makes sure that it always plays a smooth melody. And if the conductors should ever make a mistake, then the resulting sour note can lead to cancer.

Peter Laird, Ph.D., at University of Southern California's Norris Comprehensive Cancer Center, looks at one method by which cells conduct their symphony: DNA methylation, a process by which a methyl group (three hydrogen atoms bound to a carbon) is tagged onto certain stretches of a gene, thus marking them as "off." "Methylation acts like a pair of chemical handcuffs," says Laird. "The gene is intact; it's just been silenced." While DNA methylation patterns change over a person’s lifetime, a reflection of natural growth and environmental exposures, normal cells will exhibit certain unique methylation patterns, much like fingerprints. If the normal methylation patterns are altered, and the improper genes are turned on or off, then a normal cell could become cancerous. "We can use DNA methylation markers to detect cancer before symptoms arise," says Laird, "if we have a sensitive enough technique."

After arriving at USC in 1996, Laird helped design such a technique: a USC-patented technology called MethyLight, a robotic device that allows for rapid identification of DNA methylation on numerous gene sites simultaneously. With MethyLight’s high-throughput assistance, Dr. Laird is currently studying methylation markers in both ovarian cancer and esophageal adenocarcinoma.

Another researcher, Steven Libutti, M.D., who is employed by and works on the campus of the National Cancer Institute, is also using gene expression patterns as a diagnostic tool. Libutti focuses on thyroid cancer, one of the fastest growing cancers in terms of incidence. Millions of nodules, or lumps at the edge of the thyroid, are detected every year, although over 95 percent of the nodules are benign. “Currently,” says Libutti, “we assess the risk of thyroid cancer by fine needle aspiration; we insert a needle in the nodule to collect cell samples, and then examine the cell morphology to determine if they are benign or cancerous. If there is a risk, we perform a more extensive operation to remove the nodule."

Libutti points out that fine needle aspiration, like many other methods of cancer detection, has two drawbacks: many tests end up inconclusive, and the procedure itself is unpleasant and often needs to be repeated. “By using molecular diagnostics, we might be able to minimize the number of inconclusive aspirates by increasing the sensitivity of the test. This could reduce the number of procedures needed and therefore minimize patient discomfort,” says Libutti. The advantage of DNA diagnostics is that no matter where a tumor may originate, DNA evidence can be found throughout the body. “Cancer cells are constantly dying and releasing DNA into the blood,” explains Laird. While the amount of cancerous DNA is far smaller than DNA released from normal cells, PCR can amplify the desired genes of interest from blood or urine samples to determine if any genetic alterations exist.

With the help of gene chip technology and artificial neural networks, Libutti compared the gene signatures of benign and cancerous thyroid nodules, scanning for differences. “We found that the expression of only eleven genes could predict whether a lesion will be cancerous or benign,” he says. “These thyroid gene tests may also be able to determine which type of thyroid cancer – papillary, follicular, medullary, or anaplastic-- is likely to develop.”

Laird does caution that DNA changes occur so early in the development of cancer that the DNA diagnostics he and Libutti want to utilize can be a ‘grey zone’ between risk assessment and true detection. "We are trying to detect a cancer earlier than it can be seen," says Laird, "and currently, if you can’t see it, you can’t verify it." He points out that in his methylation studies, he has observed that otherwise healthy cells of people with increased cancer risks, for example the lung cells of smokers, show methylation patterns similar to cancerous cells, but that does not necessarily mean that these healthy cells will become cancerous.

Molecular diagnostics are still at a point where they are most effective when used in conjunction with standard approaches. “When we combine the expression patterns of the nodule with our analysis of the cell morphology,” says Libutti, “we can get a clearer picture and may cut down on those ‘inconclusive’ results.” DNA diagnostics are also well suited to detect cancer recurrence at an earlier stage. “For recurrence, you know exactly what you are looking for, so you can get that slam-dunk result,” says Laird. He adds, “In the next 20 years, though, I think we might develop DNA-based tests as a stand-alone diagnostic for early cancer detection.”

Molecular diagnostics can be useful for more than simply detecting cancers early. “Gene expression patterns can not only tell us if a cancer might be present,” says Libutti, “they can also tell us valuable information about the cancer.” Tumors that appear similar on the surface can be quite different molecularly, and these tests can reveal the key genes involved in driving a particular cancer; and this knowledge can help physicians treat cancer more effectively through targeted therapies.

“Chemotherapy and radiation therapy operates under the principle of killing the cancer cells,” says Mark Pegram, M.D., another NCI-funded researcher at UCLA’s Johnson Comprehensive Cancer Center. “Bombarding a patient with such a potent force is what produces all the negative side effects, such as weakness and nausea.” With a better understanding of the molecular basis of cancer, treatment strategies can change to target specific parts of the cancer machinery. “Now we have a better ability to selectively target cancer cells, thus sparing normal cellsand tissues from toxicity” says Pegram. “Even in situations where we may not be able to kill all of the tumor cells, we may be in a position to control them for long periods.”

One molecular target that Pegram looks at is the HER2 gene, which is overexpressed in about 20 percent of breast cancers. HER2 breast cancers tend to be more aggressive and fatal, because HER2 makes a protein that promotes faster cell growth. However, DNA tests can determine whether a woman has a HER2-positive breast cancer, and drugs that specifically block the protein, such as Herceptin, can inhibit cell growth. Pegram has just completed a study that combined Herceptin treatment with Avastin, a drug that prevents cancer cells from making new blood vessels to provide nourishment for the cells as they grow; in essence it “starves” the cancer cells. Pegram notes that “this combination therapy showed promising responses, even in Phase I studies, but importantly, it was easy to administer and had few side effects.”

While Pegram and other researchers who work on targeted therapies look at cancer at the individual level, other scientists such as Dennis Deapen, Dr.P.H, also at USC Norris Comprehensive Cancer Center, look at cancer genetics at a population level. Deapen, who is director of the Los Angeles County Surveillance Program, studies the trends of cancer incidence of different ethnic groups, both within Los Angeles County and California as a whole.

One of his recently completed studies examined cancer incidences between different Asian-American groups. “Before, when they were all combined under a single group, it created meaningless statistics,” says Deapen. “When you examine the incidence rates of individual ethnicities, such as Japanese, Koreans, and South Asians, you can find differences as drastic as you see between other groups such as African-Americans and whites.” Deapen and other epidemiologists hope to use increased knowledge about site-by-site cancer risks among ethnicities to improve street-level public health.

But how big of a role does genetics play in explaining the large incidence discrepancies among ethnicities? “There is certainly a gene-environment interaction for cancer,” says Deapen, “but trends data shows that for many types of cancer immigrant populations will quickly begin to assume the risk levels of L.A. county, sometimes within one generation. Obviously, their genes didn’t change that quickly.” Deapen notes that many experts estimate that lifestyle differences among ethnicities accounts for 60 to 80 percent of the observed variation in cancer incidence.

“The question of genes versus environment does remain mysterious for some cancers,” he adds. Even after taking all lifestyle factors into account, African-American men still have much higher rates of prostate cancer, whereas white men have higher rates of bladder cancer.”

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