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Recent Genetic Findings and What They Could Mean

by Cecilia Lacks, PhD

The genetic research of Dr. Catalona and his collaborators has contributed to significant findings in the genetics of prostate cancer:

EGR-1 and TRMPSS2

One finding with extraordinary potential is a gene identified as EGR-1 that is up-regulated in prostate cancer. One of the first reports on this up-regulated gene in prostate cancer was published by Dr. Catalona’s and Dr. Jeffrey Milbrandt’s group in Nature Genetics. (2003)

Up-regulated means the number of receptors for a chemical or drug on cell surfaces in a given area has changed so that the cells react more to a given protein.

Most recently, scientist Arul Chinnaiyan wrote a computer program in which he looked at all genes either up or down regulated in prostate cancer and found EGR-1 very up-regulated. Along with this finding, he discovered a gene fusion – a piece of one gene locates on another one – TRMPSS fused to the EGR-1. In examining tissue from prostate cancer patients, 80-90% had this gene fusion present.

"It’s a significant piece of the puzzle, but we’re not sure whether the fusion is the cause of the prostate cancer or associated with it. Does this fusion start the process or does it occur in cells as a result of the cancer,” Dr. Catalona said.


Hepsin

Dr. Catalona and Dr. Jeffrey Milbrandt also co-authored a paper on their findings that the protein hepsin is overexpressed in a majority of prostate cancers.

"The hope is that we've found a protein involved in the development and growth of prostate cancer. If hepsin, is involved in the actual function of the prostate cancer cell, a drug could be targeted to inhibit this protein, a drug that would be effective in the treatment of prostate cancer," Catalona said.

Since hepsin appears to be excessively produced in most prostate cancers, it is possible that chemicals developed to block the actions of hepsin could prevent prostate cancer from developing or progressing.

Both Catalona and Milbrandt are hopeful about the discovery because hepsin has so many good features for drug development.

"Hepsin is up-regulated a lot and therefore easy to knock out. Also, it’s located on the cell’s surface, which means it's easier for drugs to get to it," Catalona said.

Currently, several pharmaceutical companies are working on developing inhibitors of hepsin as a possible future treatment of prostate cancer.

RNAseL

Some of the most exciting findings from Dr. Catalona's collaborative research group are connected to the gene RNAseL, located on chromosome 1, and a variant of this gene, R46Q2, which is associated with increased cancer risk. At least one copy of R462Q is carried by nearly 60% of the men in the study.

Men who carry this variant exhibit a three-fold reduction in RNAseL enzyme activity. Researchers estimate that nearly 13% of prostate cancers may be attributable to the R462Q variant.

"Because using genetic methods for detecting the R462Q variant are already available and tests for measuring the functional activity of the RNAseL have been developed by our Cleveland colleagues, the potential is there for developing clinical tests for prostate cancer susceptibility and possible new methods of prevention and treatment," Dr. Catalona said.

Moreover, recent follow-up studies by colleagues at the Cleveland Clinic and the University of California, San Francisco suggest that the RNAseL gene may be related to a virus that is frequently associated with prostate cancer.

Genetic Marker 8q24

A group of scientists and doctors from around the world, including Dr. Catalona, participated in a study with deCODE Genetics to identify genetic risks for prostate cancer.

This study confirmed a gene marker located on chromosome 8q24 in men from Iceland, Sweden and the United States.

“ These findings may be used to develop some of the first clinical genetic tests for prostate cancer susceptibility and aggressiveness. And they may provide fundamental insights into the causes and development of prostate cancer, insights that could help us identify new molecular targets for treatment and prevention,” Dr. Catalona said.

These findings have now been replicated by a group at Harvard. The replication is a significant advance in genetic research of prostate cancer.

Taken together, these studies suggest several new genetic variants that may cause prostate cancer or may be closely linked to other as-yet undiscovered genes that cause it and make it behave in an aggressive manner.

Focused Direction

URF Board member and Quest columnist Jules Reichel described his reaction to this directed focus for genetic research into causes of prostate cancer.

“ What is most exciting to me is our scientific community is focused not on evaluating a random collection of drugs and a huge collection of theories. Intead, they have a coherent theory of the disease that they believe in and that is supported by solid study and data.

“ It is a great ribute to Dr. Catalona that he is not just a world leader in current treatment, but he is also driving hrd with a large group of the best scientific associates to convert this genetic research into a solid cure,” Reichel said.

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