Studies reveal genes key to RCC development, growth

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Two recently published Mayo Clinic studies provide genetic clues to clear cell renal cell carcinoma that may have important therapeutic implications, researchers say.

In a genomic analysis of clear cell RCC, researchers uncovered 31 genes that they say are key to development, growth, and spread of this most common form of kidney cancer. Eight of the genes had not been previously linked to kidney cancer, and six others were never known to be involved in any form of cancer.

This study is a thorough analysis, because overexpressed genes were functionally tested in kidney cancer cells to ensure they were important to some aspect of the cancer process, the study’s senior investigator, John A. Copland, PhD, of Mayo Clinic, Jacksonville, FL, said in a news release. Findings were published online in Oncotarget (June 12, 2014).

“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,” Dr. Copland said. “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.”

Dr. Copland and colleagues examined an equal number of samples (72) of normal kidney and kidney cancer tissues. They examined overexpression and underexpression of RNA from the tissue, as well as protein production. They found almost 6,000 genes that fit that description. The researchers isolated and tested 195 genes that are consistently elevated across patient samples. They then narrowed the “hit” list to 31 after testing each in living cancer cells to determine if these genes contributed to either growth or spread of the tumor.

“We also found genes with other functions that are key to kidney cancer survival, such as inflammation,” said first author Christina von Roemeling. “Another found gene is linked to angiogenesis, the production of new blood vessels to support a tumor. This is a novel discovery. It is particularly important because ccRCC is well known for being a very angiogenic cancer.

“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. “It really is a treasure trove for future research on kidney cancer.”

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One of the genes named in the Mayo Clinic group’s hit list is the subject of a second, related study by Dr. Copland and colleagues. In that study, the neuronal pentraxin 2 (NPTX2) gene, which is known to control brain growth and development, was found to be heavily involved in promoting clear cell RCC.

The study not only shows that NPTX2 is active in kidney cancer, but is the first to reveal that the gene is overexpressed in any human cancer, according to a Mayo Clinic release.

“We found that a gene known to play a role in the healthy brain is also the number one gene associated with this most lethal of all urological cancers,” Dr. Copland said. “We don’t know why NPTX2 is expressed in kidney cancer, but we now know what it is doing and how it contributes to cancer progression. We also have very promising ideas about how to attack the NPTX2 protein-which may provide a much-needed new strategy to treat this kidney cancer.”

The study was published online in Cancer Research (June 4, 2014).

From the group of 31 genes the researchers found were important to growth of clear cell RCC or its ability to survive, they determined that NPTX2 was a key gene to cancer viability. Co-author Derek Radisky, PhD, then searched for prevalence of the NPTX2 gene in kidney cancer using nine public genomic datasets, representing thousands of patients, and found it to be the top aberrantly expressed gene associated with this cancer.

The researchers also discovered that GluR4, a receptor that the NPTX2 protein usually targets in the brain, is also found in the kidney cancer samples. They found out how NPTX2 and GluR4 promote cancer growth and metastasis. In kidney cancer, the overexpressed NPTX2 protein is secreted from the cell and then attaches itself to GluR4 on the kidney cancer cell membrane.

NPTX2 causes multiple GluR4 proteins to unite and form a channel into the cell, which allows calcium to flow in. Blocking the GluR4 channels caused the cancer cells to die, suggesting a possible avenue of therapy.

“The observation that a gene such as NPTX2 that is critical to the growth of a healthy brain is also a tumor promoter in renal cell carcinoma is certainly curious,” said Urology Times Editorial Council member Leonard G. Gomella, MD, of Thomas Jefferson University and the Kimmel Cancer Center, Philadelphia. “However, we have known for some time that the same genes in different tissues can generate different forms of messenger RNA and proteins through a process known as alternative splicing.

“The challenge will be in developing an effective therapeutic agent that can target the gene or its receptor in renal cell carcinoma without harming function of the gene in normal brain tissue,” Dr. Gomella said.

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