It is no exaggeration to say that molecular geneticist, William B. “Billy” Isaacs, Ph.D., is a giant in his field, a research pioneer who has contributed greatly to our knowledge and understanding of the genetics of prostate cancer – a field he helped originate. A Google scholars search shows that Isaacs has authored or co-authored 788 papers and numerous book chapters, and has been cited in other researchers’ papers nearly 83,000 times.

Isaacs, the William Thomas Gerrard, Mario Anthony Duhon, and Jennifer and John Chalsty Professor of Urology, is retiring after more than three and a half decades at the Brady. He will be greatly missed. His longtime colleague and collaborator, Jun Luo, Ph.D., the Alan W. Partin, M.D., Ph.D. Professor in Urology, will be taking over as head of the Patrick C. Walsh Hereditary Prostate Cancer Program – a program Isaacs has led for many years.

Hereditary Prostate Cancer Research Began at The Brady

Here are some highlights of this remarkable program: In the late 1980s, Walsh, Brady resident Gary Steinberg, and M.D./ Ph.D. student Bob Carter defined and characterized hereditary prostate cancer. They established the clear link between family history and a man's likelihood of developing the disease, and laid the groundwork for the exciting research that would define Isaacs’ career.

In 1992, Carter, Walsh, and geneticists Barton Childs and Terri Beaty published a landmark study in the Proceedings of the National Academy of Science. They established for the first time the genetic basis for prostate cancer and predicted that a rare, “high-penetrance” genetic mutation would be found in families with early age of diagnosis and multiple affected family members.

This launched the partnership between Walsh and Isaacs, who joined the Brady faculty after earning his Ph.D. in the lab of renowned Brady scientist Donald S. Coffey, Ph.D. Over the last 34 years, their discoveries transformed the field. Walsh was the clinician who identified the families (more than 3,000) to be studied, and Isaacs was the scientist analyzing their DNA (more than 8,000 samples), looking for the mutations that cause the disease to be transmitted from one generation to the next. This was a Herculean task, akin to looking for one misspelled word in 20 sets of the Encyclopedia Britannica! After two decades of painstaking work, Isaacs found the gene Walsh and colleagues had predicted: in 2012, in collaboration with Kathleen Cooney at the University of Michigan, Isaacs’ research team identified HOXB13 as the first major susceptibility gene for prostate cancer.

A mutated HOXB13 gene was thought to be a risk only for men of Nordic European descent, but in 2021, Isaacs, Luo, and colleagues discovered a mutation on HOXB13 called X285K that is linked to more aggressive cancer in Black men.

In 2008, Isaacs, along with longtime colleagues Henrik Grönberg in Sweden and Jianfeng Xu at Wake Forest University (later NorthShore University), published the first paper showing the ability of five common genetic variants (called single nucleotide polymorphisms or SNPs, pronounced “snips”) to predict the risk of being diagnosed with prostate cancer. His group was also among the first to show that these SNPs contributed to the inherited risk for prostate cancer in high-risk men of African descent as well as in European men.

Building on this work, Isaacs and his team, in partnership with scientists at Howard University, began a first-in-field project to identify factors in the genome and immune system in Black men with aggressive, locally advanced, or metastatic prostate cancer.

Isaacs was part of an international study in 2020, published in European Urology, showing that men of African – but not European – descent have a particular SNP that raises the odds of developing prostate cancer. “This pretty much, hands down, is the most important genetic risk marker I’ve seen for Black men,” Isaacs said.

In 2016, in another first-of-its-kind study, Isaacs and colleagues completed a detailed genetic analysis of 96 men who died of prostate cancer at age 65 or younger. “We sequenced all regions on each chromosome that code for proteins,” Isaacs said. “Surprisingly, we found that more than 20 percent of these patients carry inherited mutations which inactivate a class of genes responsible for repairing damaged DNA.” This study and other work by Isaacs’ group and international research groups identified a short list of bad genes that appear in lethal prostate cancers. This work also changed how scientists thought about prostate cancer – because these mutated genes (most notably, BRCA1, BRCA2, ATM, and PALB2) – are also involved in the worst cancers of the breast, colon, ovaries, and pancreas. They can be inherited by men and women. For the first time, a connection was made between prostate cancer and other cancers that run in families.

Several years ago, when asked what was most important about his time at the Brady, Isaacs said: “The environment at the Brady is truly unique and astoundingly nurturing. I consider it an honor and a blessing to have had the privilege to spend my entire career in this mecca of American urology.”