Germline or somatic mutations in the BRCA1 gene might not be key to the initiation of prostate cancer, as previously thought, suggests the first study of its kind, published in BMJ Oncology. If confirmed in further studies, the findings suggest that it may be time to reassess current treatment with PARP inhibitors in men with BRCA1 genetic variants, said researchers.
Prostate cancer is the most common cancer in men, and genetic variants in DNA damage repair and response genes are known to have a role in disease progression. For example, men with inherited or acquired mutations in BRCA2 or ATM genes are at heightened risk of aggressive disease and have worse outcomes than those who do not have these mutations, researchers explained.
Study Methods
Researchers reviewed the genetic test results of 450 men with prostate cancer in North West England between 2022 and 2024 to quantify the contribution of germline and somatic mutations in different DNA repair and response genes. The men had been tested for germline (n = 166), somatic (n = 280), or both types (n = 4) of genetic variants of BRCA1, BRCA2, ATM, CDK12, and PALB2 genes, with a view to starting them on PARP inhibitor treatment.
In 340 cases, the cancer had metastasized. The average age of men in the metastatic group was 69, but patient age ranged from 38 to 87.
Among men in this group with metastatic prostate cancer who were not tested, based on high risk—age or family history—at least 18 (just over 5%) had a germline BRCA2 variant, and 1 had a germline BRCA1 (0.3%) variant. Among the 263 screened for germline ATM variants, 7 (3%) tested positive.
Genetic Variants Tested
Among the 124 undergoing germline testing based on high risk, their average age was 56 (range, 34–77 years). Again, germline BRCA2 variation predominated, with 8 (8%) testing positive, and 1 (less than 1%) testing positive for a germline BRCA1 variant.
Germline BRCA1 and BRCA2 test results were available for all 450 men. They revealed 27 germline BRCA2 variants (6%) and 2 germline BRCA1 variants (0.5%); in one of these two men, an ATM mutation was also present, noted the researchers.
Six ATM germline variants were found among the 328 men tested for this genetic mutation. Among the 97 men tested for germline PALB2 variants, one was found in a patient in his 70s who had a strong family history of breast cancer. Of those tested for CHEK2 (n = 122), for Lynch syndrome (n = 69), or for RAD51C/D (n = 15) genetic mutations, none was found.
Somatic test results were available for 280 men whose cancer had metastasized. Overall, 31 (11%) had an identifiable BRCA2 genetic variant. Of them, 16 (6%) were confirmed germline, and 11 (4%) were confirmed somatic. Variant type was unclear in four patients.
This indicates that BRCA2 variants, somatic and germline, have a major role in prostate cancer progression, affecting at least 1 in 10 carriers with the disease, researchers said. BRCA1 variants, on the other hand, do not seem to be major contributors to disease initiation or progression, with one somatic variant and one germline variant found in combination with a germline ATM variant in one case where the disease had metastasized.
Both germline and somatic ATM mutations were also associated with disease spread, as 16 of the 263 (6%) tumor samples tested had an ATM genetic variant identified, 5 (2%) of which were germline, 7 (2.5%) of which were somatic, and 4 were indeterminate.
Conclusion
The researchers acknowledged that 217 tumor samples were tested for all genetic variants, and they were unable to classify all those identified as either somatic or germline. And as the BRCA1 variant carriers were tested relatively recently, the longer-term outcomes for these men are not yet known.
The authors concluded: “The current study has shown a high frequency of BRCA2 involvement in both metastatic and familial prostate cancer.... In contrast, BRCA1 is not convincing for either somatic or germline involvement in metastatic disease in our series. Both germline and somatic ATM mutations are also associated with metastatic disease. Our data suggest that somatic CDK12 and somatic/germline BRCA2 should no longer be considered mutually exclusive.”Disclosure: For full disclosures of all study authors, visit BMJ Oncology.
