Researchers Find Genetic Secrets to Common Kidney Cancer

By examining expression of every human gene in clear cell renal cell carcinoma (ccRCC) compared to normal kidney cells, researchers at Mayo Clinic’s campus in Florida have discovered gene signatures they say explain much of the biology of this common and difficult-to-treat kidney cancer.

In the May 18 issue of PLoS ONE, the researchers report they have discovered: a biological pathway signature of ccRCC for a group of altered genes that give this distinct cancer its “clear cell” appearance; other genes that confer stem cell-like properties to the cancer; and a set of master genes lost in ccRCC that they believe likely pushes initial development of the cancer.

“Understanding these genes and the pathways they regulate could provide valuable insight into how to treat ccRCC,” says hematologist/oncologist Han W. Tun, M.D., the study’s first author.

This cancer makes up 80 percent of all kidney cancer and is often resistant to both chemotherapy and radiation treatment, Dr. Tun says. It accounts for just 3 percent of all cancers in the United States, but is the sixth leading cause of cancer death.

“Up until this point, ccRCC was largely a mystery, but now we have new and exciting clues that seem to reveal the origin and development of this cancer,” says senior investigator John Copland, Ph.D., a cancer biologist.

The research team, which included scientists from the University of Texas Medical Branch in Galveston, used a comprehensive genome-wide gene expression analysis to look at expression of about 25,000 genes in the human genome. The gene chip measures the amount of messenger RNA (mRNA) that is transcribed from genes as part of the protein production process.

They used this tool to measure levels of mRNA for each gene in tissue samples taken from kidneys that were removed from 10 ccRCC patients. The kidneys were removed at the time of surgery and contained both normal tissue as well as tumor, so the scientists compared gene expression between the two to see what genes in the cancer were either over- or under-expressed, compared to normal cells.

Researchers found that 13,729 genes had altered expression in the cancer — a figure Dr. Copland calls “just astounding, especially in trying to develop new treatments and in understanding the causes of kidney cancer.” They used novel software that grouped these genes into meaningful biological pathways — which helped them discover master genes. Each of these master genes regulates hundreds of “downstream” genes.

Researchers confirmed these gene expression findings in 20 kidneys removed from other ccRCC patients. Then, they validated gene expression at the protein level in kidneys taken from a different group of 50 ccRCC patients. To provide biological relevance, researchers then grew live normal kidney and ccRCC cells in a culture mediuam and conducted experiments

Among the research findings are: