Identifying and classifying gene mutations - which are the permanent changes in a person's DNA genetic code - are critical in better understanding, and with research, eventually treating or preventing, the diseases with which they are linked.
In a paper first posted online on April 3, 2025, in the journal European Urology Focus, a Johns Hopkins Medicine-led research team reports that it has identified a recurrent frameshift mutation, called F722fs, in the MMS22L gene among men of Ashkenazi Jewish ancestry that is associated with a higher risk of prostate cancer and increased sensitivity to a specific anticancer therapy. The MMS22L gene is involved in repairing damaged or faulty DNA.
A frameshift mutation occurs when one or more components (known as base pairs) of a DNA sequence are either inserted or deleted, causing the reading of the code to be shifted from normal.
"This is analogous to letters being added or delete from words in a sentence, so that the reading order is skewed and the meaning is corrupted," says study lead author William Isaacs Ph.D., the William Thomas Gerrard, Mario Anthony Duhon, and Jennifer and John Chalsty Professor of Urology (retired) at the Brady Urological Institute of the Johns Hopkins University School of Medicine. "In a person, a frameshift mutation may prevent a needed protein from being manufactured, underproduce or overproduce a protein to problematic levels, or create an unneeded protein - all things that may increase the risk of dveloping certain types of cancer."
In their most recent study, Isaacs and his colleagues looked at 65 germline loss-of-function (LoF) variants - mutations in a reproductive cell (egg or sperm) that cause some genes to lose their normal functions, are passed from parent to child, and may increase the risk of certain cancers - in 3,716 Ashkenazi Jewish men who had their prostate gland removed at Johns Hopkins Medicine since 1987 to treat prostate cancer. The researchers were looking to see which of those genes - and in turn, which of their LoF mutations - were associated with a higher risk of developing prostate cancer when compared with 103,221 Ashkenazi Jewish men in a control population derived from data from around the world collected for the Genome Aggregation Database.
"We found three genes with LoF mutations in the case group where the man had significantly higher rates of prostate cancer than in the control group," says Isaacs. "To validate our finding, we looked at the three genes in two groups of Ashkenazi Jewish men from a United Kingdom database - 107 who had been treated for prostate cancer and some 1,200 as a control population - and found that one of the three genes, MMS22L, continued to be linked to higher rates of the disease."
Further analysis by the researchers, says Isaacs, revealed that the vast majority of the men with prostate cancer from the Johns Hopkins and UK groups who carried the MMS22L gene also had the same LoF variant, a frameshift mutation known as F722fs.
Looking at data from three other patient groups (University of Michigan/Duke University, NorthShore University HealthSystem and GoPath Labs) of Ashkenazi Jewish men who had prostate cancer, the researchers again found a solid association with the F722fs mutation.
When all data from all sources - both with (study groups) and without prostate cancer (control groups) - were analyzed, the overall relationship between being an Ashkenazi Jewish male carrying F722fs and the likelihood of developing prostate cancer was defined using a statistical tool called an odds ratio. This is a measure of how often a specific factor occurs in a study group compared to its frequency in a control group.
A hazard ratio of 1 suggests no difference between groups, while in this case, a ratio greater than 1 indicates an increased likelihood of developing prostate cancer. Likewise, a ratio less than 1 indicates a decreased risk for the disease.
Overall, the data from all of the patient groups revealed 11 F722fs carriers out of 743 Ashkenazi Jewish men with prostate cancer - or 1.5% - and 21 with the mutation out of 6,809 Ashkenazi Jewish men - 0.3% - who had not developed the disease.
"With those percentages, we get an odds ratio of 4.9 - a significantly strong correlation between carrying the MMS22L gene and an F722fs frame mutation with a greater risk of future prostate cancer," says Isaacs.
Isaacs says that the positive correlation he and his colleagues found between the mutated MMS22L gene and prostate cancer risk in Ashkenazi Jewish men is comparable to other known DNA repair gene mutations linked to increased prostate cancer risk for that population, such as the well-known BRCA2.
Additionally, the researchers found their data indicates that Ashkenazi Jewish men with the F722fs mutation also may be linked to two other characteristics of note, one negative and the other positive.
"We learned that those with the F722fs mutation who developed prostate cancer were likely to have more aggressive forms of the disease," says Isaacs. "On the other hand, we know that the MMS22L gene makes a person more responsive to a prostate cancer treatment known as PARP inhibition, so perhaps the F722fs mutation may play a role in that sensitivity - a role that we might be able to leverage for improving the therapy. However, we did not look at that in this latest study."
In future research, Isaacs says he and his colleagues hope to learn more about the F722fs LoF mutation, especially how it might be used as a tool for both screening an Ashkenazi Jewish man's risk of developing prostate cancer and predicting which of those men will benefit most from a PARP inhibitor as part of their treatment should they get the disease.
Along with Isaacs, the members of the research team from Johns Hopkins Medicine are Oluwademilade Dairo; Marta Gielzak; Tamara Lotan; Jun Luo; Shawn Lupold; Daniel Rabizadeh; Polina Sysa-Shah; Patrick Walsh; and Guifang Yan.
Other team members are study senior author Jianfeng Xu, Brian Helfand, Zhuqing Shi, Hu Tran, Jun Wei and Siqun Zheng from NorthShore University HealthSystem; Kathleen Cooney and Nathan Snyder from the Duke University School of Medicine; and Brandon Cornell, Valentina Engelmann, Jim Lu, Lucy Lu and Qiang Wang from GoPath Labs.
The work was supported by U.S. Department of Defense, the Ambrose Monell Foundation and the Patrick C. Walsh Hereditary Prostate Cancer Fund.
