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Searching for Damaged Genes in Prostate Cancer


Jil A. Macoska, Ph.D.


Every cell in the body contains a set of basic instructions for cellular functions encoded in its genetic material, or DNA (deoxyribonucleic acid).  The DNA of one cell type is identical to the DNA of any other cell type, e.g., the DNA content of a hair cell is the same as that of a prostate gland cell.  Even so, DNA is influenced to express different stretches of its sequence (called genes) by various other types of molecules (for example, hormones, transcription factors, and growth factors) that differ from cell type to cell type.  Such differential gene expression, in fact, is ultimately responsible for cells developing into different cell types in the first place.  Just as genes can be differentially expressed in diverse cell types, they can also be differentially "damaged".  Such damage occurs through seemingly random processes such as mutations and deletions, both of which can alter the basic DNA sequence, thereby destroying the integrity of the cells' basic set of instructions.  Our laboratory is interested in finding out which genes are damaged in prostate cells, and how such damage results in the malignant transformation of normal cells into cancer cells.

The largest pieces of DNA visible to the eye with the aid of a microscope are called chromosomes.  Each cell has 22 pairs of chromosomes, called autosomes, and one "pair" of sex chromosomes (XX in females and XY in males).  Portions of one of the pairs of autosomes, chromosomes 8, appear to be especially damaged in prostate cancer cells.  Recent work in our laboratory has described three different regions of chromosome 8 that are damaged by way of deletion in the majority of prostate tumors.  Because these regions of chromosome 8 are missing in malignant but not normal prostate cells, we assume (by a rather commonly accepted definition) that they harbor certain types of genes called tumor suppressor genes.  Tumor suppressor genes are thought to be expressed in normal cells and functioning as their name implies -- suppressing the cells from transforming and growing into tumors.  Through still poorly defined mechanisms, tumor suppressor genes are sometimes turned off in cells due to inactivation by mutation or deletion.  When that happens, the affected cells are less able to elude malignant transformation, and can more easily become tumor cells.

In our laboratory, we have used two molecular biological approaches to find and characterize the tumor suppressor genes inactivated on chromosome 8 in prostate tumors.  The basic aim of both approaches is to search cancer cells for sequences that are damaged through deletion on one or both copies of chromosomes 8.  One approach is to use polymerase chain reaction (PCR) techniques to examine multiple, closely-spaced, small regions of DNA sequences along the chromosome to find those regions that are missing in cancer cells but present in normal prostate cells.  This approach initially enabled us to define three such deleted regions on chromosome 8 in prostate cancer cells, and is now being used to finely dissect those regions and zero in on the critical tumor suppressor genes.  We expect to identify the tumor suppressor genes using the criteria that they should be deleted from one copy of chromosomes 8 and mutated on the other copy, effectively "knocking out" both copies of the gene (part of the classic definition of  a tumor suppressor gene).  Another approach we use is fluorescence in situ hybridization (FISH) techniques, where we look inside individual cell nuclei to determine whether specific DNA sequences are present or absent.  This technique has the advantage of allowing us to survey tumors for different patterns of DNA sequence losses, and of revealing the relationship between individual sequence losses on chromosomes and the structural integrity of the rest of the chromosome.  For example, preliminary results from our laboratory and others suggests that loss of some chromosome 8 sequences and subsequent duplication of these damaged chromosomes is more deleterious than simple losses alone, and increases the risk for tumor recurrence.  Part of our work is focused on identifying these types of correlations between chromosomal structural, numerical alterations, and tumor recurrence.  Such correlations may someday allow prognostic tests to be developed that could identify tumors that are likely to progress and require early, aggressive treatment, from those that would likely be curable using less aggressive or invasive therapies.

Many laboratories in addition to our own are engaged in searching for damaged genes in prostate cancer.  This process has been compared to searching for a needle in a haystack due to the enormous number of genes that could potentially be affected in cancer cells.  Even so, through organizations like A.F.U.D., such research has resulted in significant advances in our understanding of basic tumorigenic processes, an understanding that will lead to better and more effective cancer therapies in the near future.

This article originally appeared on page 14 of the Summer 1996 issue of "Family Urology," published by the American Foundation for Urologic Disease (AFUD).  Dr. Macoska is a former AFUD Research Scholar (1991-1993) and recipient of the AFUD/Searle New Investigator Research Award (1995-1996).