Dr. William Isaacs

In the Spotlight

Dr. William Isaacs is Professor of Urology and Oncology at The Johns Hopkins University School of Medicine. He is the primary investigator of the Hereditary Prostate Cancer Study at the James Buchanan Brady Urological Institute at the Johns Hopkins Medical Institutions.

What are the goals of your research in hereditary prostate cancer?

We are engaged in a comprehensive search to understand why prostate cancer occurs in certain individuals and how one’s genetic makeup increases one’s risk for prostate cancer. Practically, identifying the genetic targets that are disregulated in prostate cancer gives us a better basis for clinical management of the disease through prevention, diagnosis, and treatment. So we are attempting to answer the basic how’s and why’s of prostate cancer. Our research goals are lofty, but the exciting thing is that the research can tell us so much.

What are your most recent accomplishments?

We are developing a fuller appreciation of the complexity of prostate cancer, at both the genetic and environmental levels. The genetic complexity has become very evident in that at least 5 to 6 different chromosomal regions (also called “loci”) suspected of harboring prostate cancer genes have been identified by various groups. So far, our group at Hopkins has identified regions on chromosomes 1, 8, and the X chromosome as containing prostate cancer susceptibility genes, and we are still searching for the specific genes. Myriad Genetics in Utah recently cloned and characterized a gene on chromosome 17 called HPC2, which was found to be mutated in several families with prostate cancer. However, other researchers have not seen much evidence to implicate HPC2, so its significance is unclear at present.

This complexity is also apparent in how progress in the search for prostate cancer genes compares to breast cancer genetics research. In breast cancer, we know that BRCA1 and 2 are clearly important genes accounting for as much as 80% of hereditary breast cancer. There are likely similar genes for prostate cancer, but there may be a larger number of genes, and each one individually may account for fewer prostate cancer cases. Prostate cancer also appears to be different from colon cancer, which has clinically distinct hereditary syndromes. People did not think of prostate cancer as having an important hereditary component until fairly recently mainly because the hereditary form is not that much different from the sporadic form, other than perhaps having an earlier age at diagnosis. This makes our job somewhat more difficult as prostate cancer has not been readily stratified into potentially more genetically homogeneous subsets (groups of similar cases). Now we are trying to define and stratify prostate cancer families by similar characteristics such as aggressiveness of cancer and age of onset. Recent studies suggest that when families were stratified by similar clinical characteristics, previous unclear findings were clarified and confirmed.

Another area of progress is in international collaboration. The International Consortium for Prostate Cancer Genetics is made up of 10 to 15 research groups internationally whose main goal is to study hereditary prostate cancer. The Consortium pools resources and shares data, effectively setting the stage for further progress and interaction with various researchers around the world.

What are some of the challenges that you encounter, and how could your research be facilitated?

The heterogeneity (differences) among prostate cancer patients affects the study of inherited forms of prostate cancer. When you have common diseases, you see familial clustering due to chance, shared genetic influences, or similar environmental exposures. It is necessary to distinguish between these types of prostate cancer. Making sure we have as much clinical information as possible on a patient’s prostate cancer is important in making these distinctions. Important information includes histology and grade of the tumor, the stage of cancer, the prostate specific antigen (PSA) level, and the age of the patient. We can use this information to stratify the prostate cancer types and then focus on cancers we feel are "clinically significant".

As we become more sophisticated, we also want to know the interactions between genetics and epidemiology, lifestyle, and ethnicity. Understanding susceptibility to prostate cancer in the context of environmental exposures is an important challenge to tackle. An individual with the same genetic make-up as a person affected with prostate cancer may not get the disease because he is not subjected to the same environment. Ethnicity is a further contributing factor. For example, African American men are more likely to get prostate cancer. But even among the African American population, there is much heterogeneity. We want to determine which aspects of heritage are the determinants of disease so we can understand prostate cancer progression and how it is affected by the environment.

Good data collection, the ability to collaborate with others, and willingness to share and pool data so that we can generate and test hypotheses are important facilitators of research in prostate cancer.

How will your research impact prostate cancer patients and their families?

Once a patient is diagnosed with prostate cancer, his disease can take a variable course. This can make it challenging for a physician to decide how to approach treatment. There are many treatment options depending on the level of tumor aggressiveness, including surgery, radiation, and chemotherapy. Treatment decisions are informed by findings from the tumor biopsy and the patient’s family history. However, specific information on the genetic variation leading to cancer development can help to predict more carefully what the cancer will do and what the prognosis will be.

Many men are also concerned for their children’s cancer risk. Right now, we tell members of the families we are studying who are not yet affected that they are at risk and recommend more frequent screening. But it would be more informative to counsel them with better information. The current extent of our knowledge is that men in families with prostate cancer have a higher chance of getting the disease and that the more men who have the disease in the family, the higher the risk. If we knew specifically what gene or gene product was involved, then we could develop a test to screen for the mutation and quantify the risk. Though there is the chance that knowing more may increase psychological anxiety, we would at least like to have this option since people who are predisposed generally want to know their risk. The idea is that if we understand and can identify a group of people highly likely to develop the disease, we can intervene before the cancer begins or progresses. In certain cases even prostate removal may be a reasonable preventive measure in that the prostate glad is not essential for normal life. From the work of Drs. Bill Nelson and Paul Talalay here at Hopkins, it is apparent that certain aspects of diet may play an important preventive role for prostate cancer.

What are the future directions in hereditary prostate cancer research?

The science of the Human Genome Project and the availability of the human genome sequence have changed our ability to understand normal variation and how it contributes to disease susceptibility. This new information advances the methodology and technology by which we can screen individuals for any disease risk. It is now an attractive possibility to develop a profile of DNA variation, like a fingerprint, by looking at a large number of genes when screening individuals. In families, one usually thinks of a single gene affecting the manifestation of prostate cancer. However, we are learning that a summation of various weaker genetic effects may affect cancer development. Today, we can do case-control studies and look for more subtle changes (called polymorphisms) using high throughput genetic technology. In prostate cancer, some current evidence suggests that polymorphisms in the hormone synthetic pathways may affect the levels of various hormones (e.g. testosterone) produced, leading to increased risk for prostate cancer.

In the future, we would like to continue international collaboration. A major facilitator of research is the willingness of people to come forward and get involved in these studies as researchers and participants. It is noteworthy that in colon cancer and breast cancer research, a few critical families provided the final key insight in determining the responsible genes.