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Conquest - Cracking Genome Codes, Finding Unlikely Answers

Making the Connection 2001-2008

Cracking Genome Codes, Finding Unlikely Answers

Date: April 20, 2010

CRF Making Headlines in 2006

Scientists have completed the first draft of the genetic code for breast and colon cancers. Their report, published online in the September 7, 2006, issue of Science Express, identifies close to 200 mutated genes, now linked to these cancers, most of which were not previously recognized as associated with tumor initiation, growth, spread or control.
“Just as sequencing the human genome laid the groundwork for subsequent research in genetics, these data lay the foundation for decades of research on colon and  breast cancers,” says CRF investigator VICTOR VELCULESCU, M.D. , PH.D. Although gene discoveries by independent scientists scattered around the world have provided clues, Velculescu says relatively few genes have been shown to be altered in cancers. The Hopkins gene hunters, which also included CRF investigator BEN PARK, M.D. , say the number of genes that were altered in breast and colorectal cancer genomes surprised them.
These findings will guide and provide support for future comprehensive genetic studies including those envisioned by The Cancer Genome Atlas Project. Future research will include performing similar analyses on other tumors types, charting the pathways through which each mutant gene acts, and looking for common mutations that can be targeted with
therapy. ?

Men firing up their backyard grill may be getting an extra unwanted condiment with their mustard and ketchup, and it could lead to prostate cancer—namely 2-amino-1-methyl- 6-phenylimidazo [4,5-b]pyridine, or PhIP. The compound forms in meats cooked at very high temperatures, such as those cooked over flames.

Previous animal studies showed that rats fed food mixed with PhIP had more gene mutations and precancerous lesions in the ventral lobe located in the front of the prostate gland than rats not fed the compound. New data reported by the American Association of Cancer Research shows inflammation, a known contributor to development of many types of cancer, was also noted in the ventral lobes of the PhIP-fed rats, says study leader and CRF investigator ANGELO DEMARZO, M.D. “For humans, the biggest problem is
that it’s extremely difficult to tell how much PhIP you’ve ingested, since different amounts are formed depending on cooking conditions,” says study collaborator and CRF investigator WILLIAM NELSON, M.D. , P H . D. “As a result, it has been difficult to fully determine how much human prostate or other cancers might be caused by PhIP.”

Johns Hopkins and Georgetown University researchers conducted a meta-analysis of 18 epidemiologic studies revealing that women who eat soy products may have a slightly lower risk of developing breast cancer. But the researchers quickly added that inconsistencies and limitations among the studies raised doubt about the potential benefit, and warned women that high-dose supplements could do more harm than good. “At this point, women should not be taking high-dose soy supplements if they are breast cancer survivors or at increased risk for the disease,” says CRF investigator BRUCE TROCK,
PH.D. “We don’t have long-term data on the effects of these supplements, and there is some evidence that they could be harmful.” Tests of refined soy products in animals revealed increased tumor growth, and short-term studies of women taking the supplements showed changes in breast cell growth that might actually increase risk for breast cancer.

Results of the review by Trock and his colleagues at Georgetown University, published in the April 5th issue of the Journal of the National Cancer Institute, found inconsistencies among the studies. Many differed in whether or not—or how—they accounted for the many factors that may impact development of breast cancer, such as body mass index (BMI). Studies that took BMI into account showed that soy had less of a protective effect than those that ignored BMI. “This is consistent with the idea that people who eat a
lot of soy most likely eat fewer calorieheavy foods and are less likely to have high BMI,” explains Trock. “This means that breast cancer risk may not be due to eating soy products, but to other dietary or lifestyle factors.”

After averaging results from the studies, which span a quarter century, researchers found that the overall relative reduction in breast cancer risk for soy eaters was a modest 14 percent in Caucasian women. The effect was not statistically significant in Asian women. Differences in pre- and postmenopausal women were slight and potentially biased
 due to the small number of studies that accounted for menopausal status. Trock says that definitive studies, that track participants over time and before they get cancer, may take decades. For now, Trock says there is no problem with adding soy to the diet since it has health benefits regardless of whether it protects against breast cancer. “The important aspect is eating actual soy-based foods like tofu, not highly purified isoflavone supplements,” he adds. “Highly refined components of soy can have very different
biological effects than eating tofu or drinking soymilk.” Instead of pill supplements,
Trock suggests replacing some meats with soy foods such as tofu, soy milk or soy nuts for people who want to add soy to their diet. ?

A small but significant studying focused on a protein called EPCA for early rostate cancer antigen. Blood tests for the marker predicted prostate cancer with 94 percent accuracy, compared to 25 to 30 percent accuracy for PSA. A larger trial of 600 men is now under way.

In other research, CRF investigators ANGELO DEMARZO, M.D. , P H . D. ,
and WILLIAM NELSON, M.D. , PH.D. , found that prostate cancer cells express lower levels of the protein GSTP1. They are now working on a test to measure GSTP1 levels in blood. ?

CRF researchers ANTHONY ALBERG , PH.D. , M . P. H . , and CONNIE TRIMBLE, M.D. , report that secondhand smoke increases a woman’s risk of cervical cancer. Their study of more than 50,000 women found that those who lived with smokers had a 40 percent or greater risk of developing cervical cancer. ?

A quirky muscle protein known as myosin VI may help prostate cells become cancers and help them stay that way. In laboratory studies of human prostate cancer cells, investigators, including CRF researcher ANGELO DEMARZO, M.D. , PH.D. , found overproduction of myosin VI in prostate cancer cells and precancerous prostate lesions. When they altered the cells to shut down production of myosin VI, the cells lost some of their cancer characteristics. Their results, published in the November 2006 American Journal of Pathology, suggested that myosin VI may be critical in starting and maintaining the malignant properties of the majority of human prostate cancers diagnosed today. The
investigators found that among 59 samples of benign and cancerous prostate tissue,
myosin VI expression was almost four times higher in prostate cancer samples than in normal prostate tissue samples. What’s more, they found that overproduction of the protein occurs early in cancer development, including common precancerous prostate disorders known as PIN (prostatic intraepithelial neoplasia) and PIA (proliferative inflammatory atrophy). DeMarzo says, “Creating a laboratory test to identify high or low levels of myosin VI in urine or blood might aid in the early detection of prostate cancer.” ?

Investigators led by CRF researcher SHYAM BISWAL, PH.D., discovered how taking the brakes off a “detox” gene causes chemotherapy resistance in a common form of lung cancer. Products made by a gene called NRF2 normally protect cells from environmental
pollutants like cigarette smoke and diesel exhaust by absorbing the materials and pumping them out of the cell. Another gene called KEAP1 encodes products that stop this cleansing process. But lung cancer cells sabotage the expression of these same genes to block assault from chemotherapy drugs.

“What we’re seeing is that lung cancer cells recruit and distort NRF2 and KEAP1 expression to help tumor cells evade the toxic effects of chemotherapy,” says Biswal, who published results of cell culture studies in the October 3, 2006, issue of PLoS Medicine.

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