Battling Prostate Cancer

We recently had the opportunity to speak with Dr. William B. Isaacs of Johns Hopkins, whose research focus lies in hereditary prostate cancer. He told us of the search for the elusive prostate cancer genes.

Interest in hereditary prostate cancer research at Johns Hopkins was initiated by Dr. Patrick Walsh, chair of the Department of Urology. He realized that there were families with clusters of prostate cancer. He was particularly impressed with diagnoses of prostate cancer in young men with strong family histories of the disease. Noting that early onset and family history were typical of inherited syndromes, Walsh began surveying his patients about family history of prostate cancer and used the spouse's family as the control group. He found that having a first-degree relative with prostate cancer increased one's risk by two-fold and having multiple family members raised the risk 7-10 fold. He also found that the younger the age of onset, the higher the risk. Similar results were found in the 1960s in the Mormon studies, and researchers in the 1980s found that prostate cancer clusters actually occurred more often than breast or colon cancer. However, while it was common for people to think about a family history of breast or colon cancer as a risk factor, people were not concerned about a family history of prostate cancer.

In the early 1990s, an MD-PhD student named Bob Carter, who received his doctorate from The Johns Hopkins School of Public Health in Epidemiology, came to Dr. William Isaacs' lab to work on the molecular analysis of somatic alterations in prostate cancer. His interest in familial clustering led him to perform the first segregation analysis of prostate cancer on the subjects of Walsh's case-control study. He attempted to see if the familial clustering was due to a shared environmental influence or a genetic component. Based on Mendelian inheritance patterns, Carter estimated that 9% of prostate cancer could be explained by genes. For early onset disease occurring before age 55, he estimated that 40% could be due to genetics. Carter's landmark work was the first formal statement of the possible existence of prostate cancer susceptibility genes in the population.

In 1993, Walsh sent a letter to all 5,000 members of the American Urological Association stating that Hopkins was interested in collecting families that may be harboring a prostate cancer susceptibility gene. He presented the criteria of early onset and multiple affected members as indications of families that may be of interest. The letter was instrumental in capturing the attention of urologists and succeeded in drawing numerous referrals. Hopkins also got a tremendous response to an article in Parade magazine about Walsh and his surgical prostatectomy procedure that had a little blurb about hereditary cancer.

By 1995, thanks to the many referrals from physicians responding to Walsh's letter and to the efforts of Sally Isaacs, study coordinator and sister-in-law, Dr. William Isaacs and colleagues had enough families to start genotyping and performing linkage analysis. They began by looking at regions in candidate genes like BRCA1 and MSH2 that had been linked to other cancers, but to no avail. Their next step was to perform a systematic scan of the entire genome. Who better to join forces with than the National Human Genome Research Institute (NHGRI), those working on the Human Genome Project? They formed a collaboration with Jeff Trent and Francis Collins, scientific director and director of NHGRI, respectively. They identified several regions that suggested evidence of a prostate cancer gene, particularly a locus on chromosome 1. After confirming with additional families from Hopkins and Sweden, provided by Henrik Gronberg, they published a paper in the October 1996 issue of Science suggesting a susceptibility locus for prostate cancer on chromosome 1. Since then they have identified another locus on the X chromosome. These are the two loci they are currently trying to clone, but it has been a difficult task.

Why is Dr. Isaacs interested in hereditary prostate cancer genes, especially when the disease is often slow growing and late-onset? If he can map the genes that signify which men are likely to develop the disease and which men are going to have fast progressing disease, then he can make well-informed decisions on how to treat them. The bottom line is to be able to identify men at high risk in order to screen them early and treat them early. Ultimately, Dr. Isaacs wants to prevent prostate cancer.

Isaacs William B. Isaacs joined Johns Hopkins in 1977 as a lab technician for Donald Coffey, director of the Brady Urological Research Laboratory. He went on to receive his doctorate from The Johns Hopkins University in the Department of Pharmacology and Molecular Science. Dr. Isaacs then left Hopkins to do a post-doctoral program at the University of Iowa, but returned in 1988 to join the faculty of the Department of Urology.