The Genetics of Higher Risk

In 1992, Brady investigators were the first to characterize and define hereditary prostate cancer (HPC). We now know that inherited genetic factors play a role in about half of all men with prostate cancer, and account for at least 10 to 15 percent of prostate cancer deaths.

Recently, groundbreaking work by William Isaacs, Ph.D. and colleagues showed that it’s not just prostate cancer-specific genes that put a man at risk:

DNA damage repair genes – known to raise the risk of other cancers – also raise a man’s risk of dying of prostate cancer eightfold. “To reduce deaths from prostate cancer, we must identify men at risk of lethal prostate cancer when cure is still possible,” says Patrick Walsh, M.D., who was Director of the Brady for three decades. “The best way to do that is through genetic testing.”

Since 2018, Isaacs and his team have sequenced more than 6,000 complete exomes (all the protein-coding segments in the genome) from men with prostate cancer. “Due to the disproportionately high risk of prostate cancer in Black men, we focused first on this population, and completed next-generation sequencing of more than 1,600 Black men,” says Isaacs, the William Thomas Gerrard, Mario Anthony Duhon and Jennifer and John Chalsty Professor of Urology.

Early results are promising: “In this population, we have tentatively identified about 50 candidate genes with mutations – genes that were not previously thought to play a role in prostate cancer development.” In addition to these new genes, Isaacs’ team, in collaboration with scientists at the University of Southern California, has identified “SNPs,” variant genetic sequences, in Black men; this work was published in European Urology.

Work by the team, including Isaacs’ long- time collaborator, Jianfeng Xu, Ph.D., of NorthShore Research Institute, has resulted in 22 peer-reviewed publications in prostate cancer genetics over the last three years.

Predicting Multifocal Cancers:

More than 80 percent of primary prostate cancers are “multifocal;” they harbor two or more distinct sites of origin. Could this tendency be inherited? Isaacs, Xu, and Brady colleagues Christian Pavlovich, M.D., the Bernard L. Schwartz Distinguished Professor in Urologic Oncology and Urology resident Yasin Bhanji, M.D., conducted a first-of-its- kind study to answer this question.

The investigators sequenced hundreds of SNPs known to be associated with prostate cancer risk to determine a genetic risk score (GRS), for more than 1,200 patients in active surveillance programs at Hopkins and NorthShore, and compared these findings with results of prostate biopsies.

They found that patients with a higher GRS are likely to have more positive tumor cores and bilateral (on both sides of the prostate) tumors. These results, published in The Prostate, suggest that inherited genetics can affect “whether a patient’s prostate is likely to harbor multiple sites of cancer – and possibly,” says Isaacs, “even where these cancer lesions are most likely to be located!”

These findings could make prostate biopsies smarter and more effective. Several retrospective studies by the group have shown that adding GRS can improve detection rates in high-risk men, while reducing unnecessary biopsies in others.