Imagine a zipper: it works great, as long as the metal tracks are perfectly lined up. But if just one tiny piece of metal goes askew, the whole zipper gets derailed.

Something similar can occur in DNA: it’s called a “frameshift mutation,” and what happens, explains molecular geneticist William Isaacs, Ph.D., is like “adding or deleting letters from words in a sentence. The words become skewed, and the meaning is corrupted.” Isaacs, recently retired as the William Thomas Gerrard, Mario Anthony Duhon, and Jennifer and John Chalsty Professor of Urology, is the lead author of a Hopkins-led study published in European Urology Focus. In it, he and colleagues reported the discovery of a frameshift mutation that has important implications for men of Ashkenazi Jewish ancestry.

This mutation, called F722fs, happens in a gene called MMS22L – a DNA repair gene, similar to the BRCA genes, whose job is to fix errors in the genetic code. When these repair genes are out of service, those errors don’t get fixed. In this case, “men with the F722fs mutation have a higher risk of developing certain types of cancer, including prostate cancer,” says Isaacs. But there’s a silver lining: drugs called PARP inhibitors (olaparib, rucaparib, and others) specifically target and are more effective in cancers with this kind of genetic damage. Cancers with a DNA repair gene mutation depend on a protein called poly (ADP-ribose) polymerase, or PARP, which acts as a sort of genetic tool kit to keep them going. PARP inhibitors block access to these patch-up repairs – so the cancer cell can’t divide, and dies.

In the study, the team looked for 65 known cancer-linked inherited mutations, called “loss of function (LoF) variants,” in 3,717 men who had prostate cancer and were treated with prostatectomy at Johns Hopkins, compared to a control group of 103,221 men from around the world, using information from the vast Genome Aggregation Database.

Initially, “we found three genes with LoF mutations where the men had significantly higher rates of prostate cancer than in the control group,” says Isaacs. To validate this finding, they looked at those three genes in two UK databases of men who had been treated for prostate cancer and a control group. “We found that one of these genes, MMS22L, was linked to higher rates of prostate cancer.” In further study, the team found that “all the men with prostate cancer from the Hopkins and UK groups who had a faulty MMS22L gene had this same F722fs variant. Importantly, an examination of ancestry-informative markers revealed that all carriers were of Ashkenazi Jewish ancestry.”

They broadened their search again, looking at data from Ashkenazi Jewish men in three other patient groups – University of Michigan/Duke University, NorthShore University HealthSystem, and GoPath Labs – and again found a higher risk of prostate cancer in men with the F722fs variant.

Like having a bad BRCA2 gene: Men who inherit a mutated MMS22L gene “are not only more likely to develop certain cancers, including prostate cancer – but possibly to develop more aggressive cancer, and to develop it at a younger age,” says Isaacs. “On the other hand, recent findings from other researchers at Harvard strongly suggest that the MMS22L gene, like a mutated BRCA2 gene, makes a person more responsive to PARP inhibition. It may be that the F722fs mutation contributes to PARP sensitivity as well.”

In future research, the team will seek to confirm these findings using independent data sets. In addition, Isaacs and the team hope to explore the potential role of the F722fs mutation as a target of genetic screening, and also as a predictor of response to PARP-inhibiting drugs.

This work was supported by the U.S. Department of Defense, the Ambrose Monell Foundation, and the Patrick C. Walsh Hereditary Prostate Cancer Fund.