• The Brady Urological Institute

The Genetics of Higher Risk

Research led by Dr. Patrick C. Walsh and Dr. William B. Isaacs

The Brady Urological Institute, Johns Hopkins University School of Medicine

November 2021

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, made possible by support from the Ambrose Monell Foundation and federally supported grants, 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. “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 has identified “SNPs,” variant genetic sequences, in increasing risk for Black men. One exciting discovery is HOXB13, a mutated gene initially discovered by Isaacs in 2012 that greatly raises a man’s risk of getting prostate cancer: a new stop loss mutation shows a strong tendency to be associated with risk for more aggressive, early onset disease in African American men. This novel finding is highly translatable to the clinic for the important task of prostate cancer risk stratification.

Work by the team has resulted in 22 peer-reviewed publications in prostate cancer genetics over the last three years. The team will continue to pursue confirmatory data for the candidate prostate cancer susceptibility genes with the goal of better identifying, counseling and treating those who are at higher risk of aggressive disease.

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