Previously in Discovery, we reported on the work of William Isaacs, Ph.D., the William Thomas Gerrard, Mario Anthony Duhon and Jennifer and John Chalsty Professor of Urology, and colleagues showing that inherited mutations in a few genes involved in repairing damaged DNA are significantly more common in men who die from metastatic prostate cancer, compared to men who have less aggressive, more slow-growing cancer.

Since then, Isaacs’ research group has worked to understand more about mutations in these genes, including BRCA2 and ATM. “We wanted to find out whether there was a correlation between mutations in genes associated with lethal disease and the grade of prostate tumors,” says Isaacs.

In a collaborative study with Ambry Genetics, the scientists studied 1,694 men who underwent radical prostatectomy at Johns Hopkins, including 708 patients with the two highest tumor grades (grade groups 4 and 5) and 988 patients with lowgrade (grade group 1) disease. They looked for mutations in 14 DNA repair genes – the genes Isaacs and his group previously had shown to be most commonly mutated in metastatic prostate cancer.

“Overall,” Isaacs says, “we found that the number of men carrying inherited (germline) mutations in the 14 genes was significantly higher in patients with high-grade disease,” compared to men with the lowest-grade cancer. “We also found that three genes, ATM, BRCA2, and MSH2, were mutated at a much higher rate in high-grade cancers.”

Isaacs and colleagues were surprised to find that men in grade group 5 had about 20 times the number of mutations as men in grade group 1, and three to six times more mutations than men in grade group 4. “While much more work is necessary, the strong enrichment of mutations in these three critical DNA repair genes and tumors among men in grade group 5 is greater than expected,” says Isaacs. “This suggests a fundamental association between loss of normal tissue architecture, acquisition of aggressive tumor behavior, and inherited inactivation of specific, key components of critical DNA repair pathways.” Better understanding of this association “could provide a basis for novel, gene-targeted treatment.”