Department for BioMedical Research, University of Bern, Bern, Switzerland.
Institute of Pathology, University of Bern, Bern, Switzerland.
Nat Commun. 2022 May 3;13(1):2400. doi: 10.1038/s41467-022-30003-5.
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.
通过更有效的治疗方法，前列腺癌的生存率得到了提高，这也导致了转移到不常见部位（如大脑）的诊断增加。在这里，我们研究了 51 例前列腺癌脑转移（PCBM）患者脑转移灶中存在的体细胞遗传改变谱。我们强调了 PCBM 中发生的克隆进化，并证明与非脑转移相比，PCBM 的突变负担增加，同时同源重组缺陷突变特征富集。我们关注同源重组修复基因中的已知致病性改变，发现 10 名患者（19.6%）符合 PROfound 临床试验中使用的纳入标准，该试验评估了 PARP 抑制剂（PARPi）在同源重组缺陷前列腺癌中的疗效。8 名患者（15.7%）表现出试验中包含的 15 个基因之一的双等位基因缺失，而 5 名患者（9.8%）特异性地存在 BRCA1/2 的致病性改变。揭示 PCBM 的这些分子特征可能具有治疗意义，表明在评估 PARPi 的潜在获益时，需要对 PCBM 患者进行临床试验登记。
