Genes That Drive Clear-Cell RCC Discovered, Providing Research Clues

John A. Copland, PhD

A genomic analysis of renal cell carcinoma (RCC) has uncovered new clues about the development, growth, and spread of the cancer.

The analysis, which was published online June 12 in the journal Oncotarget, targeted the clear-cell form of the disease, which comprises 80% of cases, and found 31 genes that are key in causing and spreading the cancer. Eight of the genes had not previously been linked to renal cancer, and six others were not previously linked to any cancer, according to a press release from the Mayo Clinic News Network.

Mayo described the analysis as the most extensive to date on the role of gene expression in clear-cell RCC (ccRCC). “The power of this study is that we looked at genes discovered to be overexpressed in patients’ tumors and determined their function in kidney cancer, which has not been done on a large scale before,” the study’s senior investigator, molecular biologist John A. Copland, PhD, stated in the press release. “This is a seminal step in identifying key pathways and molecules involved in kidney cancer so that specific therapies that target these new genes can be developed to treat this cancer.”

While the prognosis for kidney cancer that has not spread is good, patients with advanced or metastatic disease will develop drug resistance. Those with untreated metastatic disease have a 5-year overall survival rate of <10%, according to the release.

“We are releasing these discoveries to the scientific community so that a large effort can be mounted to find out more about these genes and how they can be effectively targeted,” Copland said. “We owe patients speedy research that focuses on new treatments to save lives.” New treatments might be less toxic than existing targeted therapies for the disease, he added.

The investigators found the relevant genes by comparing samples of tissue with and without kidney cancer (72 samples each) and looking for under-or-overexpression of RNA and protein production in the samples with cancer. In a high-throughput genetic analysis coupled with a high-throughput proliferative screen, they found about 6000 genes of interest, then isolated and tested 195 that were consistently elevated in patient samples. Finally, the researchers tested the genes in living cancer cells to see if they contributed to the growth or spread of disease; that reduced their list to 31 genes required for ccRCC cell propagation.

“We also found genes with other functions that are key to kidney cancer survival, such as inflammation. Another found gene is linked to angiogenesis…This is a novel discovery,” said Mayo Clinic graduate student and lead study author Christina von Roemeling. “It is particularly important because ccRCC is well known for being a very angiogenic cancer.”

In addition to angiogenesis, many of the isolated genes are implicated in metabolism, differentiation, and cell motility in other cancer systems, the authors wrote in their paper. “Of these, we further establish a role for CDH13 in tumor angiogenesis, as well as a promigratory role for four novel factors, including KISS1R, KSR1, CAMK1, and SSPN in ccRCC,” they wrote. Little is known, so far, about the protein function of several of these gene products, they noted. Von Roemeling agreed that the findings will have important research implications.

“In addition to the potential of these genes and gene products to help us design new drugs, they could also serve as biomarkers for accurate diagnosis,” she said in the press release. “It really is a treasure trove for future research on kidney cancer.”