Mutations in the BRCA1 gene, long considered a potential driver of prostate cancer, might not be as important as previously thought, according to new research. The study, published in BMJ Oncology, reveals that both germline and somatic BRCA1 mutations do not appear to play a significant role in the initiation or progression of prostate cancer, contrary to current thinking that these mutations could be key to the disease’s development.
“Mutations in the BRCA1 gene that are either inherited (germline) or acquired (somatic) might not be key to the initiation of prostate cancer, as previously thought,” noted a press release from the research team led by Emma Woodward, PhD, consultant clinical geneticist at the Manchester Centre for Genomic Medicine in England.
If the findings are confirmed, they could lead to a reassessment of treatments such as the use of PARP inhibitors to target BRCA1. PARP inhibitors have been touted as a potential treatment for men with BRCA1 mutations, as these mutations are believed to affect DNA repair mechanisms. However, the study’s findings suggest that prostate cancer patients with BRCA1 mutations may not benefit as much from PARP inhibitor therapy as previously thought.
The discovery also has implications for genetic testing in prostate cancer. Currently, testing for BRCA1 mutations is common for assessing prostate cancer risk, particularly in cases where there is a family history of the disease. But with this finding from this new research, with BRCA1 mutations appearing less central to the disease, the focus could shift to other genes, such as BRCA2 or ATM, which the study found to be more strongly associated with aggressive forms of prostate cancer.
For this research, the investigators analyzed genetic data from 450 men with prostate cancer in North West England between 2022 and 2024. Of these, only two men were found to carry germline BRCA1 variants, compared with 27 men who had BRCA2 mutations and 16 men with ATM mutations.
“The current study supports the major involvement of BRCA2 in metastatic prostate cancer,” the researchers wrote. “BRCA1 variants, on the other hand, don’t seem to be major contributors to disease initiation or progression.” These data suggest a potential move away from PARP inhibitors to those drugs that target DNA repair pathways associated with BRCA2 and ATM genetic alterations.
An editorial accompanying these findings, written by Fumihiko Urabe, MD, PhD, a clinical associate in the department of urology at Jikei University School of Medicine in Tokyo, and Kosuke Takemura, MD, a clinical fellow at the Tom Baker Cancer Centre, Calgary, also noted that the “newly demonstrated limited involvement of BRCA1 suggests that tumors harboring BRCA1 variants may not rely on homologous repair deficiency, potentially limiting their responsiveness to PARP [inhibitor]-based therapies.”
“In breast and ovarian cancers, both BRCA1 and BRCA2 mutations occur at high frequencies, and the patterns vary across cancer types. In drug development, the molecular targets for therapies addressing BRCA1 and BRCA2 mutations have been largely the same. As a result, the distinct characteristics and significance of BRCA1 and BRCA2 mutations have not been thoroughly investigated,” Urabe and Takemura continued. “However, in prostate cancer, the frequencies of BRCA1 and BRCA2 mutations differ substantially, making it worthwhile to examine them separately.”
The next steps to confirming these findings will include further genetic analysis of prostate cancer patients, including those with less common mutations, and longer-term studies to assess how these mutations impact treatment outcomes. The authors noted that the “findings pave the way for refining genetic testing strategies and personalized treatment approaches in prostate cancer.”
