Posted: Jun 07, 2016
In the 1990s, we were just starting to recognize that prostate cancer clusters in families. Soon it was clear that family history is a strong risk factor for prostate cancer. In fact, the three most important prostate cancer risk factors are age, race, and family history. Despite extensive research on other risk factors, these three remain the most significant.
The fact that prostate cancer runs in families could be chance or it could be the result of shared environment or another type of exposure. But genetics also seems a likely cause for some of the familial clustering of prostate cancer. This hypothesis led many investigative teams, including my own, to try and identify families with multiple cases of prostate cancer. We used those families to conduct linkage studies looking for segments of DNA that harbor genes that might be relevant to hereditary prostate cancer. This research, however, has proved much more challenging than initially anticipated.
Some of the family studies in prostate cancer were based on research on other common cancers like colon and breast cancer. In these cancers, linkage studies were quite successful in helping us identify key genes that are not only important for risk assessment in families, but also for providing knowledge about the basic biology of cancer.
Finding prostate cancer genes has been difficult for a number of reasons. First, prostate cancer is a late-onset disease. Often, by the time a man is diagnosed with the disease, other family members who may have also had the disease are already deceased. Obtaining access to these older medical records is often challenging. Another problem is that we have had variable ways of diagnosing prostate cancer over the past 30 years. With the introduction of PSA testing to find early-stage or asymptomatic disease, there was a dramatic increase in the number of prostate cancer cases in the US. Men with prostate cancer were encouraged to have their male siblings screened for prostate cancer and this made it more difficult to identify the hereditary cancers. This over-diagnosis of prostate cancer in family members complicated our field for a long time since we cannot differentiate between genetic cancers and sporadic or nongenetic cancers in terms of clinical factors.
The National Cancer Institute (NCI) supports groups working in prostate cancer genetics, including the International Consortium for Prostate Cancer Genetics (ICPCG), which has been funded for 15-20 years to collaborate on studies of hereditary prostate cancer. Our laboratory participates in this consortium to identify prostate cancer genes.
In 2012, our laboratory, in collaboration with Dr. Bill Isaacs at Johns Hopkins University and others, successfully used family-based approaches to identify a recurrent mutation in the HOXB13 gene. Additional studies by us, and others, suggest that this recurrent mutation accounts for about 5% of hereditary prostate cancer families worldwide. The protein encoded by this gene is important in prostate development. It’s still not clear what the mutations in the HOXB13 gene do to increase prostate cancer risk, but it is probably one of the more important findings in hereditary prostate cancer because it demonstrated our ability to use families and linkage studies to isolate a prostate cancer gene.