Previously in Discovery, we reported that the first-known prostate-specific cancer susceptibility gene, HOXB13, identified in 2012 by Brady scientist William Isaacs, Ph.D., and colleagues – had thrown researchers a curve ball: For a decade, HOXB13 was thought to pose risk for men of Nordic European descent only, because its G84E mutation is absent in men of African ancestry.

But then a new mutation was found on this gene: this one, called X285K, is linked to aggressive prostate cancer in Black men. As Isaacs states, “X285K is quite possibly the most important marker identified to date for lethal prostate cancer risk in men of African descent.” This work, funded by donors to the Patrick C. Walsh Hereditary Prostate Cancer Program, was published in the British Journal of Cancer.

Now, Brady scientist Jun Luo, Ph.D., the Alan W. Partin, M.D., Ph.D. Professor of Urology, is investigating this mutation in new research funded by a grant from the Department of Defense.

X285K, explains Luo, is a “stop-loss” mutation: it alters the gene’s molecular machinery and keeps adding amino acids, “totally ignoring the ‘stop sign’ of its normal cell cycle. When this mutation occurs, HOXB13 becomes much longer than normal; this stop-loss mutant is also driving prostate cancer growth by affecting other genes.”

Think of a mile-long freight train, running amok. There may be ways to stop this train: slow it down, or uncouple some of the cars to make it more manageable. “We are hoping to learn enough to find out its vulnerabilities,” says Luo, “and this might lead to gene-targeted precision treatment for prostate cancer patients with this inherited mutation.”

Scientists Mayuko Kanayama, Emmanuel Antonarakis, Tamara Lotan, Angelo De Marzo, and Arthur Burnett also contributed to this work. The team is now working with colleagues in Jamaica and Martinique to study the clinical features of patients carrying this mutation.