The Academy: September 2007

By Prachi Petal-Predd
Published: Monday, Jul 12, 2010

     Gene Fusions Switch on Prostate Cancer

Researchers at the University of Michigan Comprehensive Cancer Center in Ann Arbor have found a family of gene fusions that can cause prostate cancer. Knowing which gene fusion is involved in a patient’s prostate cancer could make it easier to tailor treatment, according to Arul Chinnaiyan, MD, PhD, Director of the Michigan Center for Translational Pathology, and lead author of the new study presented in the August 2 issue of Nature.

Dr. Chinnaiyan and his colleagues have discovered that pieces of two chromosomes can trade places with each other, causing two genes to fuse. The composite gene overrides the switch that controls cells from growing uncontrollably and causing prostate cancer.

From tests in mice and cell cultures, the researchers found that five genes from the same family can become scrambled and fuse with either ERG or ETV1, two genes that are known to be involved in different types of cancer. The researchers found such abnormal gene fusions in 60% to 70% of the prostate cancer cell lines that they studied.

The five genes are regulated differently, the research team found. Some genes are regulated by androgen, some are repressed by androgen, and some do not respond to the hormone. “This suggests that there are different types of prostate cancer,” Dr. Chinnaiyan told Oncology and Biotech News. “Some may benefit from antiandrogen therapy, but some may get worse with antiandrogen treatment and some may not get affected at all.”

Fused genes are known to play a role in cancers such as leukemia, lymphoma, and Ewing’s sarcoma. In 2005, Dr. Chinnaiyan and others were the first to show that gene fusions were the causative agents in solid prostate tumors. Just as the drug Gleevec (imatinib mesylate) targets a fused gene that plays a role in chronic myeloid leukemia, knowledge about prostate gene fusions could lead to treatments for prostate cancer, Dr. Chinnaiyan believes. “These gene fusions will be useful biomarkers for the presence of prostate cancer,” he said.

The researchers are now developing processes to detect the gene fusions by testing patients’ urine. This would be helpful for doctors to determine what kind of gene fusion is causing a patient’s prostate cancer so that they can tailor the androgen-based treatment. “This is still in the future,” Dr. Chinnaiyan said, “but somebody could get a biopsy and their gene fusion subtype could be detected and that could be used to guide their treatment.” Ultimately, he said, the goal is to target the gene fusions directly, just as Gleevec does in chronic myeloid leukemia.


     New, Powerful Lung Tumor Suppressor Gene Found

Researchers have found a new lung tumor suppressor gene for non–small-cell lung cancer in mice. The gene, called LKB1, may be more powerful than other, better-known tumor suppressors, the researchers report in an August 5 Nature paper.

In mice, the researchers found that mutations in this gene led to more aggressive tumors that are more likely to spread. If LKB1 is found to have a tumor-suppressing effect in human lung cells, it could influence the way lung cancer is diagnosed and treated, according to the study’s senior author Kwok- Kin Wong, MD, PhD, a physician–researcher at the Dana-Farber Cancer Institute in Boston, Massachusetts.

People born with mutations in LKB1 often develop Peutz–Jeghers syndrome, which increases the risk for certain cancers, and non-inherited LKB1 mutations have been found in some lung cancers.

The researchers studied lung cancer development in mice with abnormal LKB1, and compared it with disease development in animals with mutations in two other wellknown tumor suppressor genes, p53 and Ink4a/Arf. The animals had a defective Kras gene, which leads to the formation and growth of lung cancer. The researchers found that the defective Kras gene worked more strongly with the mutated LKB1 than with the other genes.

“The LKB1-deficient tumors grew more rapidly and spread more frequently than the others, and comprised all three types of non–small-cell lung cancer—squamous cell carcinoma, largecell carcinoma, and adenocarcinoma—rather than just one or two,” Wong said.

The researchers also examined 144 human non-small cell lung cancer tissue samples and found that about 34% of lung adenocarcinomas and 19% of the squamous cell carcinomas contained abnormal versions of the gene.


     Two-Drug Combo for Kidney Cancer

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