Alterations in homologous recombination repair genes in prostate cancer brain metastases

Abstract

Improved survival rates for prostate cancer through more effective therapies have also led to an increase in the diagnosis of metastases to infrequent locations such as the brain. Here we investigate the repertoire of somatic genetic alterations present in brain metastases from 51 patients with prostate cancer brain metastases (PCBM). We highlight the clonal evolution occurring in PCBM and demonstrate an increased mutational burden, concomitant with an enrichment of the homologous recombination deficiency mutational signature in PCBM compared to non-brain metastases. Focusing on known pathogenic alterations within homologous recombination repair genes, we find 10 patients (19.6%) fulfilling the inclusion criteria used in the PROfound clinical trial, which assessed the efficacy of PARP inhibitors (PARPi) in homologous recombination deficient prostate cancer. Eight (15.7%) patients show biallelic loss of one of the 15 genes included in the trial, while 5 patients (9.8%) harbor pathogenic alterations in BRCA1/2 specifically. Uncovering these molecular features of PCBM may have therapeutic implications, suggesting the need of clinical trial enrollment of PCBM patients when evaluating potential benefit from PARPi.

Plexin-B1 Mutation Drives Metastasis in Prostate Cancer Mouse Models

“…Somatic missense mutations in Plexin-B1 have been detected in patient samples of prostate cancer metastases (26). Recent studies have shown a PLXNB1 mutation rate of around 5% (ranging from 3.3% (27), 3.4% (28), 4.9% (29), to 7.8% (30) (cBioportal), compared to 9.8%, 6.8%, 2.4% and 13.7% in PTEN in the same studies. Functional analysis in vitro of three such mutations (T1697A, T1795A, L1815P), demonstrated that these sequence changes inhibit the interaction of Rnd1, Rac and R-Ras with Plexin-B1 and block the ability of Plexin-B1 to mediate R-Ras inactivation (26,31).…”

Micelle encapsulation zinc‐doped copper oxide nanocomposites reverse Olaparib resistance in ovarian cancer by disrupting homologous recombination repair

“…Interestingly, MEnZn‐CuO NPs were found for the first time as metal nanoparticles to negatively regulate the expression of HR repair pathway genes in tumors with defective HR repair capacity. However, our current study has not yet identified the targets of MEnZn‐CuO NPs to regulate the HR repair in tumor cells 50 . Homologous recombination deficiency (HRD) is the first phenotypically defined predictive marker for therapy with PARP inhibitors in ovarian cancer.…”

“…The HR repair plays an important role in the combination strategy of PARP inhibitors. Mutations in the key HR repair pathway genes BRCA1, BRCA2, and ATM are often critical for PARP inhibitor sensitization 47–50 . It has been reported that CDK4/6 inhibitors can induce DNA damage and genomic instability, which in turn can have a synthetic lethal effect with PARP inhibitors.…”

“…However, our current study has not yet identified the targets of MEnZn-CuO NPs to regulate the HR repair in tumor cells. 50 Homologous recombination deficiency (HRD)…”

PARP inhibitors in metastatic prostate cancer: When, who, and how?

“…While intraductal variant and neuroendocrine differentiation are suggestive of an underlying HRD mutation, they have no predictive capacity over or independent of genomic testing. [76][77][78][79][80] While the usage of platinum sensitivity as a marker of BRCAness is established in serous ovarian carcinoma, extrapolation of the same to carcinoma prostate is challenging since platinum-based chemotherapy is not a standard frontline option. However, two series have reported impressive outcomes in carcinoma prostate HRD patients when treated with platinum-based therapy.…”