Scientists link a rare genetic mutation to aggressive prostate cancer risk and possible better outcomes with targeted drugs. Credit: SciTechDaily.com
A newly identified mutation
dramatically raises prostate cancer risk in Ashkenazi Jewish men and may
increase sensitivity to targeted cancer therapies.
This genetic clue not only
improves our understanding of inherited cancer risks but could also inform
personalized treatment strategies using drugs like PARP inhibitors.
A Breakthrough Discovery in Prostate Cancer Genetics
Understanding gene mutations,
permanent changes in our DNA,
is a key step toward detecting, treating, and eventually preventing the
diseases they may cause. These mutations can disrupt how our bodies function at
the most fundamental level, and scientists are working to uncover which ones
matter most.
In a new study published in European Urology Focus, researchers from Johns Hopkins
Medicine have identified a specific mutation that could play a major role in
prostate cancer. This mutation, known as F722fs, appears in the MMS22L gene,
which is responsible for repairing damaged DNA. The team found this mutation in
men of Ashkenazi Jewish descent and linked it to a significantly higher risk of
developing prostate cancer. Even more intriguing, this same mutation may also
make cancer cells more vulnerable to a specific type of treatment.
How Frameshift Mutations Disrupt DNA
A frameshift mutation like F722fs
occurs when a few pieces of the DNA code are either added or lost. That small
change throws off the entire sequence, much like inserting or deleting letters
in a sentence can scramble its meaning.
“This is analogous to letters being
added or deleted 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 developing certain types of cancer.”
A Deep Dive Into LoF Mutations
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.”
F722fs Emerges as the Prime Suspect
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.
A Strong Genetic Signal
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.
One Mutation, Two Important Clues
Additionally, the researchers found
that their data indicates that Ashkenazi Jewish men with the F722fs mutation
may also 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.”
Future Research and Therapeutic Potential
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.
Reference: “Discovery of a Recurrent
Frameshift Ashkenazi Jewish Founder Mutation (F722fs) in the PARP
Inhibitor–sensitive MMS22L Gene
Associated with Higher Risk of Prostate Cancer” by William B. Isaacs, Jun Wei,
Marta Gielzak, Qiang Wang, Nathan A. Snyder, Siqun Zheng, Guifang Yan, Lucy Lu,
Valentina Engelmann, Daniel Rabizadeh, Polina Sysa-Shah, Brandon Cornell,
Zhuqing Shi, Huy Tran, Shawn Lupold, Tamara Lotan, Oluwademilade Dairo, Patrick
C. Walsh, Brian T. Helfand, Jim Lu and Jianfeng Xu, 3 April 2025, European Urology Focus.
DOI: 10.1016/j.euf.2025.02.007
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.
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