Study Challenges of the BRCA1 mutation role at the onset of prostate cancer

Mutations in the BRCA1 gene either inherited (germ line) or acquired (physically) may not be crucial to the onset of prostate cancer, as previously considered, indicates the first study of this kind, published on the Internet in OPEN magazine Access BMJ oncology.

If confirmed in further studies, the findings indicate that it may be time to reassess current treatment with PARP (ADP-Ribose) inhibitor (ADP-Ribose), which impedes cell capacity, including cancer cells, to repair the damage DNA in men with BRCA1 genetic variants, the researchers say.

A connected syntax suggests that the findings pave the way for greater improvement in genetic tests and a personalized treatment for men with prostate cancer.

Prostate cancer is the most common cancer in men, and genetic variants in repair and rehabilitation and response genes are known to have a role in developing the disease.

For example, men with hereditary or acquired mutations in BRCA2 or ATM genes are at increased risk of aggressive disease and have worse results than they do not have these mutations, the researchers explain.

To try to quantify the contribution of hereditary and acquired mutations to different DNA repair and response genes to men with prostate cancer, the researchers examined the results of 450 men’s genetic tests with the disease in northwestern England between 2022 and 2024.

Men were either tested for the germ line (166), physical (280) or both types (4) genetic variants of BRCA1, BRCA2, ATM, CDK12 and PALB2 genes, with the aim of initiating treatment with a Parp inhibitor.

In 340 cases, men’s cancer had spread elsewhere (metastasis). Their average age was 69, but ranged between 38 and 87.

Among them in this not-tested group, based on high-risk age or family history-at least 18 (just over 5%) had a BRCA2 Variation of Brca2, but only 1 had a BRCA1 variant (0.3%) germ. And out of the 263 shooting for germ line ATM variants, 7 (3%) were positively tested.

Among the 124 undergoing high risk-based germ-based tests, their average age was 56 (range 34-77). Again, the BRCA2 variant of the germ line is dominated, with a positive test 8 (8%), but only one (less than 1%) positive test for a BRCA1 variant of the germ line.

The results of the Germline Brca 1 and BRCA 2 tests were available for all 450 men. These revealed 27 variants of BRCA2 Germline (6%), but only 2 BRCA1 Germline variants (0.5%) and one of them was probably not the driver as an ATM mutation, note the researchers.

Six variants of ATM stem line were found among the 328 men tested for this genetic mutation. And among the 97 men tested for Palb2 Germline variants, just 1 found a man in the 1970s with a strong family history of breast cancer.

Of those tested for Chek2 (122), Lynch (69), or RAD51C/D genetic mutations, no one was found.

The results of physical tests were available for 280 men whose cancer had spread elsewhere. In total, 31 (11%) had a recognizable BRCA2 genetic variant. Of these, 16%were confirmed and 11 (4%) confirmed physically. The type of variant was unclear at 4.

This shows that BRCA2 variants, physical and stem lines, play an important role in the development of prostate cancer that affects at least 1 in 10 carriers with the disease, the researchers say.

BRCA1 variants, on the other hand, do not seem to contribute significantly to the onset or progression of the disease, with only 1 physical variant and 1 stem variant found in combination with an ATM variant of the germ line in a case where the disease had spread elsewhere.

Both germ line and ATM body mutations were also associated with the spread of the disease to 16 of the 263 (6%) tumors examined had a genetic variant ATM, of which 5 (2%) were germination, 7 ( 2.5%) of which they were syncs, while 4 were indefinable.

And the data indicate that the body CDK12 and the BRCA2 body and stem line should no longer be considered mutual, as they are previously.

Researchers acknowledge that only 217 volume samples were tested for all genetic variants and that they were unable to classify all those identified either as physical or germ lines. And as BRCA1 variants have been tested relatively recently, the long -term results for these men are not yet known, they point out.

“Even if there is a signal for non -metastatic prostate cancer in BRCA1, this may not justify PSA [prostate specific antigen] Control, given the high percentage percentages, “the researchers say.

“So it may be time to question whether BRCA1 should be regarded as a prostate cancer predisposition gene, given its very low prevalence in the present study of physical mutations,” they suggest.

In a connecting editorial, Drs Fumihiko Urabe and Kosuke Takemura, respectively, the Jikei University Medical School, Minato, Japan and JFCR Hospital of the Cancer Institute, Tokyo of Japan.

“[They] Strengthen the role of BRCA2 and ATM as key decisive factors of aggressive prostate cancer phenomena. BRCA1’s limited participation indicates that tumors hosting BRCA1 variants may not be based on counterpart repair, possibly limiting their response to PARP [inhibitor]-The treatments, “Write the authors.

They add: “CDK12 mutations, which were previously considered mutually exclusive with BRCA2, were observed in combination with BRCA2 mutations, indicating the possibility of dual targets that combine Parp [inhibitors] and immunotherapy. ”

And the offer of the same potential for aggressive illness in both BRCA1 and BRCA2 is probably no longer appropriate, they suggest.

“Although many previous clinical studies have categorized BRCA1 and BRCA2 mutations as a group (BRCA1/2), this research leads to the conclusion that BRCA1 and BRCA2 should be analyzed separately,” they say.

“If the post -HOC analyzes of previous clinical trials that grouped BRCA1/2 mutations reveal different therapeutic effects, it may require the re -examination of the interpretation of BRCA1 and BRCA2 mutations on prostate cancer,” they add.

Although further research is justified in more different patient groups, the findings of the study “pave the way for strategic genetic tests and personalized treatment approaches to prostate cancer,” they conclude.